Form 1. Particulars of the project and investigator(s)

Transcription

Form 1.
Particulars of the project and investigator(s)
Project No.:A65037-2
EUDRACT No.: 2008-003860-21
1. Project title
A comparative pharmacokinetic study of sublingual misoprostol after oral mifepristone in pregnant
women.
2. Principal investigator(s)
Name(s) : Dr. Oskari Heikinheimo
Position : Associate Professor, Senior Physician
Postal address : Department of Obstetrics and Gynaecology, Helsinki University Central Hospital
PO Box 140, 00029-HUS, FINLAND
Telephone : +358 40 5871070
3. Institution responsible for the research project
Name: Department of Obstetrics and Gynaecology,
Postal address: Helsinki University Central Hospital
PO Box 140, 00029-HUS, FINLAND
Telephone: +358 40 5871070
Fax: +358 9 471 74801
E-mail: [email protected]
5. Responsible financial officer
Name: Seppo Pakkala
Address: Clinical Research Institute HUCH Ltd., Helsinki, Finland
Name of institute’s bank: Nordea Bank
Bank address: Helsinki, Finland
Bank account number:
6. Duration of project
Earliest starting date (if applicable): 1 February 2009
Total (years): One
Version 2, 19 December 2008
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7. Funds requested (€)
8. Approval of ethics committees
A. Is institutional ethical clearance document attached?
Yes
B. Is documentation of Finnish Drug Regulatory Agency approval attached?
Yes
9. Acceptance of responsibility
If this application is accepted, I (we) declare that I (we) shall be actively engaged in, and shall be in dayto-day control of, the project; and I (we) agree to provide detailed annual progress reports to WHO of
the work undertaken. I (we) agree to follow the policies of the Special Programme on the dissemination
of research results. The research conducted will conform to the international guidelines for biomedical
research involving human subjects and the international principles for biomedical research involving
animals.
Signature(s) of principal investigator(s) and date:
_____________________________________________
__Oskari Heikinheimo___________________________
__Helsinki _______________________
10. Declaration(s) of the Director of the institution (or a designated representative) and the officer
responsible for the administration of funds awarded (e.g. Finance Officer, Bursar, etc.)
We confirm that this application has been approved by our institution and that, if granted, the work will be
administered in the institution in accordance with its general conditions. The staff gradings and salaries
provided are correct and in accordance with the normal practice of the institution.
Head of the institution
Administrative authority
Name and initials
Name and initials
(please print) Maija Haukkamaa
(please print) Seppo Pakkala_______________
Title Administrative Head_____________
Title Director____________________________
Institution
Institution
Department of Obstetrics and Gynecology__ Clinical Research Institute HUCH Ltd_________
Date
_________________________
Signature __________________________
Date
________________________________
Signature_______________________________
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Form 2.
Project summary
2.
Project Summary
2.1
Justification for the project
The present study aims at studying the pharmacokinetics of misoprostol following
sublingual administration. The original formulation of misoprostol will be compared with a
new generic misoprostol formulation that is co-packaged with mifepristone. It is necessary
to demonstrate bioequivalence to regulatory authorities.
2.2
Proposed research
The proposed project is a pharmacokinetic study that involves a minimum of 60 women
with a duration of pregnancy up to nine weeks. Mifepristone (200mg) will be administered
orally. Twenty four hours later two doses of 400 μg of misoprostol will be administed at 20
minutes interval sublingually. Blood samples will be collected for 6 hours following the
administration of misoprostol. The assay of misoprostol acid will be undertaken and
various pharmacokinetic parameters calculated.
2.3
New features
This will allow the registration of sublingual use of a generic preparation of misoprostol, as
the preferred prostaglandin for use with mifepristone for medical abortion.
2.4
Technique and skill
The study requires the clinical facilities and expertise to carry out medical abortion,
venepuncture, preparation of blood samples and analysis of misoprostol.
2.5
Problems anticipated
No special problems are anticipated.
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Form 3.
Description of the project
Note: Start the description of the project on this page and then continue on additional sheets as necessary.
3.1
Rationale and objective of the study
3.1.1
Rationale
The use of mifepristone together with misoprostol has become the most common method of
medical abortion. In the USA and many countries in Europe, the registered dose of mifepristone is
the original dose of 600mg used with a prostaglandin. However, given the evidence from
multicentred studies (WHO, 2002), in most countries, a significantly lower dose of mifepristone
(200mg) is used, followed by 4x200μg of misoprostol given intravaginally. For example, this is the
regimen recommended by the Royal College of Obstetricians and Gynaecologists (RCOG) in the
United Kingdom (RCOG, 2004).
Misoprostol is now the most common prostaglandin to be used in combination with mifepristone
and has been shown to be more effective and better tolerated when administered vaginally rather
than orally (El-Refaey, 1995; WHO, 2003). Moreover, in a review of outcomes in 4,132 women in
Aberdeen, when a dose of 800μg of misoprostol is given intravaginally, 3/1000 had a continuing
pregnancy (Ashok, 2002). A similar rate is seen from WHO multicentred studies, while in the
same studies, there was a rate of 12/1000 continuing live pregnancies is found after orally
administered misoprostol (800μg initial dose, followed by 800μg daily for 7 days) (WHO, 2003).
Furthermore, vaginal administration has significantly less side effects. This makes intravaginal
administration safer in situations where there is no backup with vacuum aspiration available.
Although intravaginal administration of misoprostol is the currently approved and most widely used
regimen in early abortion, alternative routes of administration (namely sublingual and buccal) are
being researched. Two studies (Tang OS et al, 2003; Hamoda H et al, 2003 & 2005) suggest that
sublingual administration of misoprostol may be even more effective than vaginal administration.
Moreover, there were no continuing pregnancies in the sublingual groups and complete abortion
rates were higher than in the vaginal groups. However, prostaglandin-related side-effects were
greater with sublingual use than with vaginal administration of misoprostol.
WHO is currently carrying out a randomized placebo-controlled 15-centre trial to compare two
doses (400µg and 800µg) and two routes of administration (sublingual and vaginal) of misoprostol
after pre-treatment with mifepristone (200mg) for early pregnancy termination (up to 9 completed
weeks of gestation). It is anticipated that some 3000 women will be recruited into the study for the
study and the final results should be available soon after its completion in July 2008. Being able to
offer the choice of sublingual and vaginal administration of misoprostol not only will provide an
additional choice to women but also possibility of an even more effective regimen.
The World Health Organization has previously licensed intellectual property, in the form of clinical
trial data to the non-profit organization, the Concept Foundation, Bangkok. Under this agreement,
the Concept Foundation committed to find a high quality pharmaceutical company which will
manufacture a copackaged product containing 200mg of mifepristone and 800μg of misoprostol,
which can be provided to the public sector of developing countries at a price of less than US$4.
Concept Foundation has achieved WHO’s requirements and together with Sun Pharma, the fifth
largest pharmaceutical manufacturer in India has been developin a full ICH-compliant registration
dossier that for submission to regulatory authorities in both developed and developing countries.
As part of this work, a bioequivalence study was undertaken in Helsinki in which 69 women
requesting medical termination of an early (≤9 weeks of pregnancy) unwanted pregnancy were
randomized to receive either the original mifepristone tablets, Mifegyne, from Exelgyn and the
original misoprostol tablets, Cytotec, from Searle or mifepristone and misoprostol, manufactured
and co-packaged by Sun Pharma, India. This study has been completed and the pharmacokinetic
data are being analyzed. The new study builds on this study and evaluates the sublingual
administration of misoprostol with the same two formulations of misoprostol.
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3.1.2
Objective
To demonstrate compare the pharmacokinetics of misoprostol following sublingual administration
of a new generic misoprostol (co-packaged with mifepristone) with the original formulation of
misoprostol.
3.2
Similar studies
No comparative pharmacokinetic study comparing sublingual administration of generic and the
original formulation of misoprostol, administered following oral mifepristone, for medical abortion
has been undertaken.
3.3
Design and methodology
3.3.1
General outline
A minimum of 60 women will be recruited into the study from those women requesting termination
of pregnancy by medical abortion at the Helsinki University Central Hospital. The hospital
undertakes some 1,200 medical abortions a year. The objectives of, and procedures involved in,
the study will be discussed with them.
Mifepristone (200mg) will be administered orally on day 1. At 24 hours, 2 tablets of 200μg tablets
of misoprostol will be administered sublingually followed by another 2 tablets of 200 μg 20
minutes later. Blood samples will collected at 15 minute intervals for two hours and then at 3, 4
and 6 hours after misoprostol administration, calculated from the first dose.. The pharmacy of the
Helsinki University Central Hospital will be responsible for the storage, packaging, randomization
and distribution of the study medications.
3.3.2
Inclusion criteria
Subjects admitted to the study will fulfil the following criteria:
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good general health
older than the legal age of consent
on day one of the study (day of mifepristone administration) the duration of pregnancy is
not more than 63 days (counted from the first day of the last menstrual period) in a normal
28-day cycle
the duration of the pregnancy corresponds to the length of amenorrhea when verified by
ultrasound, if the gestational length according to ultrasound measurements differ by more
than four days, the ultrasound dating will be used
the pregnancy is single and intrauterine (single sac)
if treatment with misoprostol should fail, subject agrees to surgical termination of
pregnancy
willing and able to participate in the study once the objective and study requirements have
been explained
3.3.3 Exclusion criteria:
Subjects will not be recruited if any of the following conditions are present:
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allergy towards mifepristone or misoprostol
a history or evidence of disorders that represent a contraindication to the use of
mifepristone (chronic adrenal failure, severe asthma uncontrolled by corticosteroid
therapy, inherited porphyria)
a history or evidence of disorders that represent a contraindication to the use of
prostaglandins (mitral stenosis, glaucoma, sickle cell anaemia, diastolic pressure over 90
mmHg, bronchial asthma, arterial hypotension)
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•
a history or evidence of thrombo-embolism, severe or recurrent liver disease or pruritus of
pregnancy
•
has any medical condition or disease that requires regular treatment with systemic drugs,
care or precaution in conjunction with abortion
tendency of abnormal bleeding (such as von Willebrandt’s disease)
the presence of IUD in utero
previous surgery of uterus/uterine cervix is a relative contraindication, however, previous
low-segment caesarean section is not a contraindication
suspicion of any pathology of pregnancy (eg, molar, non-viable pregnancy, threatened
abortion)
suspected or known breast or genital neoplasia
breast-feeding
where difficulties are anticipated in follow-up.
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Women older than 35 years, who smoke less than 20 cigarettes per day, have diastolic pressure
of less than 90 mmHg and who have no known risk factor for cardiovascular disease, can be
recruited into the study.
In addition, subjects who have been admitted into the study, will be excluded from the final
analysis, if there is evidence of:
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3.3.4
the use of drugs, other than those prescribed by the investigator for the treatment of
possible therapy-related side-effects. Pain will be managed with premedication of 1g
paracetamol and 30mg codeine, if required, NSAIDs or opiates will be given for additional
pain medication
any violation of the study protocol
essential data missing from the subject’s records making it impossible to judge the
treatment outcome
the presence of an acute illness of any nature during the treatment period.
Subject allocation
The subjects will be randomized by computer-generated random numbers into two groups. The
random table will be generated by the Head Pharmacist, Helsinki University Central Hospital.
Group A will comprise women who will be given 200mg of mifepristone produced by Exelgyn,
followed 24 hours later by two doses of 2 tablets of 200μg misoprostol produced by Pfizer. Group
B will comprise women who will be given 200mg of mifepristone and two doses of 2 tablets of
200μg misoprostol produced by Sun Pharma.
3.3.5
Description of the drugs to be used
International Non-proprietary Name: Mifepristone (Mifegyne, Exelgyn and Medabon, Sun Pharma)
Chemical name: 11β-[p-(dimethylamino)phenyl]-17β-hydroxy-17-(1-propynyl)
estra-4,9-dien-3-one
Route of administration: oral
Amount: 1 x 200mg tablet
International Non-proprietary Name: Misoprostol (Cytotec, Pfizer and Medabon, Sun Pharma)
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Chemical name: 7-[3-hydroxy-2-(4-hydroxy-4-methyl-oct-1-enyl)-5-oxo-cyclopentyl]
heptanoic acid
Route of administration: sublingual
Amount: 4 x 200 μg tablets
3.3.6
Admission procedure, treatment and sampling schedule
Before admission to the study, potential subjects will undergo the following:
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ultrasound examination to verify the length of the pregnancy and check that the pregnancy
is intrauterine. If the pregnancy is more advanced, if the there is a suspicion of an
abnormal pregnancy (eg, extra-uterine, molar, etc) the woman will not be admitted into the
study
haemoglobin measurement
blood group and Rh typing
medical, obstetrical and gynaecological history
medical and gynaecological examination
Women who fulfil the admission criteria, are willing and able to participate in the study and have
given their signed informed consent will be included in the study.
The study will be performed over a period of two days during the medical termination of
pregnancy.
Day one
Baseline blood pressure, pulse rate, body height and weight will be taken. Medical and obstetrical
history, as well as informed consent, will be obtained. The subjects will be randomized by
computer-generated random numbers into 2 groups. Each woman will then be given 200mg of
mifepristone orally. Following ingestion of mifepristone women are free to leave the hospital.
Day two (24h after oral administration of mifepristone)
An intravenous catheter suitable for multiple blood sampling will be inserted. A venous blood
sample (10ml) will be collected before misoprostol administration; this will be the 0min sample
prior to misoprostol. Two tablets of 200μg misoprostol will then be administered sublingually. After
20 minutes the tablets can be swallowed if they have not melted and another two tablets will be
administered sublingually. Venous blood samples (10ml) will be taken at 15, 30, 45, 60, 75, 90
and 105min and 2, 3, 4 and 6 hours after administration of misoprostol. All blood samples will be
centrifuged without delay and serum will be immediately frozen and stored at -20ºC. Blood
pressure, pulse and any reported side effects will be monitored.
The interval from the administration of misoprostol to onset of abdominal pain/vaginal bleeding
and passage of production of conception will be recorded. The research nurse will stay with the
subjects throughout the blood taking procedure to provide emotional support and counselling if
necessary. It is anticipated that some 90% of subjects will have aborted by six hours after the
administration of misoprostol. Some subjects will abort before six hours, in which case no further
blood samples will be collected. Surgical evacuation will be performed if there is excessive
bleeding due to incomplete abortion.
Control visit
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Study subjects will be requested to return for a control visit, two to three weeks after treatment at
which a pelvic examination and ultrasonography will be performed. If the subject is found to have
a continuing pregnancy, surgical evacuation will be performed. The results of all the tests relevant
for the on-going care of the woman will be available to the treating physician.
3.3.7 Assessment of outcome of treatment
The primary outcome of the study will be to ascertain the bioequivalence of the two formulations of
misoprostol following sublingual administration. This is determined by the measurement of the
pharmacokinetic parameters, maximum serum concentration (Cmax), time to maximum serum
concentration (tmax) and area under the curve (AUC) in each study group.
The secondary outcome will be the efficacy (defined as the proportion of complete abortions in
each study group) and side effects of each of the two product regimens. The complete abortion
rate and the induction to abortion interval will also be compared. Adverse events, if any, will be
analyzed on an intention to treat basis.
3.3.8
Criteria for discontinuation
Of individual subjects
Individual subjects will be discontinued if the woman:
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•
wishes to withdraw from the study
develops severe abdominal pain and heavy vaginal bleeding, at which point the pregnancy
will be terminated immediately by surgical evacuation. Heavy vaginal bleeding presenting
an immediate threat to the patient’s health will be based on the judgement of the attending
physician
Of the study
If two or more subjects develop the same symptoms requiring discontinuation of the treatment and
the principal investigator has good reason to believe and/or evidence to show that this (these)
symptom(s) is (are) treatment-related, further recruitment will be suspended. The
decision whether or not the study should be discontinued for this reason will be taken after
discussion between the principal investigator and the Concept Foundation
3.3.9
Analysis of samples
Misoprostol acid
The samples will be stored at below -20ºC and then sent in three batches to AAI Pharma GmbH &
Co. KG laboratories (Neu-Ulm, Germany) for assay.
Misoprostol acid (MPA) will be determined using liquid chromatography/tandem mass
spectrometry (LC/MS/MS). The method is based on that of Yu Zou et al. (2007). Following liquid–
liquid extraction, the analytes are separated using an isocratic mobile phase on a C18 column. A
tandem mass spectrometer with an ionization source is used as the detector and operated in the
negative ion mode. Multiple reaction monitoring using the precursor to product ion combinations of
m/z 367–249 and 296–269 is performed to quantify misoprostol acid and the internal standard
hydrochlorothiazide, respectively. The method is linear in the concentration range, 10.0–
3000 pg/ml using 200μl of serum. The lower limit of quantification is 10.0 pg/ml.
3.3.10 Data management and analysis
The serum levels of misoprostol acid will be recorded for each time interval and the
pharmacokinetic parameters, maximum serum concentration (Cmax), time to maximum serum
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concentration (tmax) and area under the curve (AUC) will be calculated for each subject. Data
analysis will be done as recommended by the EMEA for bioequivalence studies (EMEA, 2002).
The statistical method for testing bioequivalence is based upon the 90% confidence interval for
the ratio of the population means (test/reference), for the parameters under consideration. This
method is equivalent to the corresponding two one-sided test procedure with the null hypothesis of
bioequivalence at the 5% significance level (EMEA, 2002). Pharmacokinetic parameters derived
from measures of concentration, eg AUC, Cmax will be analyzed using ANOVA. Prior to analysis,
the data will be transformed using a logarithmic transformation. Tmax will also be calculated but this
analysis will be non-parametric and applied to untransformed data. For all pharmacokinetic
parameters, in addition to the appropriate 90% confidence intervals for the comparison of the two
formulations, summary statistics such as median, minimum and maximum will be given.
3.3.11 Number of subjects
European Medicines Agency recommendations for bioequivalence studies (EMEA, 2002), section
3.6.1 Statistical analysis, state: 'The statistical method for testing bioavailability (e.g.
bioequivalence) is based upon the 90% confidence interval for the ratio of the population means
(Test/Reference) for the parameters under consideration.' … For the AUC-ratio, 'the 90%
confidence interval… should lie within an acceptance interval of 0.80-1.25.' It is also indicated that
'the data should be transformed prior to analysis using a logarithmic transformation.”
Therefore, for bioequivalence, 0.80 < Test mean/Reference mean < 1.25 or, in the logarithmic
scale, -0.22 = ln (0.80) < ln (Test mean) – ln (Reference mean) < 0.22. Bioequivalence will be
demonstrated if the 90% confidence interval for the difference between means in the logarithmic
scale is contained in -0.22-0.22 (margin of bioequivalence is 0.22).
To obtain the SD in the transformed scale, the following approximate formula was used:
Var(g(x)) = [dg(x)/dx]2 Var(x) = [dln(x)/dx]2 Var(x) = (1/x)2 Var(x), so that SD[ln(x)] ≈ SD(x)/x.
A standard formula for sample size calculation for equivalence was used (Jones B et al, 1996).
Misoprostol:
From a study conducted assess the administration of misoprostol (Tang et al, 2002), the AUC for
the vaginal route for 10 women had a mean of 433 pg.h/ml with a SD of 182. SD = 182/433 = 0.42
on a logarithmic scale. To obtain 80% statistical power with a 2-sided confidence interval of 90%,
approximately 63 women would be needed in each arm to establish bioequivalence of the two
misoprostol products within a margin of 0.22 in the logarithmic scale, which corresponds to the
90% confidence interval for the AUC-ratio within the interval of 0.80-1.25. The power obtained with
30 subjects in each arm will be 52%.
While 30 subjects/arm is in line with the recently completed pharmacokinetic study comparing the
generic formulations of mifepristone administered orally and misoprostol administered vaginally
with their original counterparts, it is uncertain whether it sufficient for assessing the
bioequivalence of two formulations of misoprostol following sublingual administration. It is
therefore proposed to recruit a total of 60 women (30 subjects/arm) and undertake an interim
analysis. Should the data indicate that an adequate power has been achieved to ascertain the
bioequivalence of the two formulations of each drug, the study will be terminated. If not, based on
the data obtained, the number of additional women required will be calculated and the study
continued to achieve this.
3.3.12 Duration of project
The trial will require about 6 months for sample collection from the initial 60 women and a further 2
months to complete the assays of misoprostol and data analysis. It will be extended if determined
to be necessary from the interim analysis.
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3.4
Assessment of safety
3.4.1
Side-effects
The use of mifepristone and misoprostol is associated with documented side-effects which have a
causal relationship with the treatment. These side-effects include nausea, vomiting, diarrhoea,
fatigue, dizziness, fainting, headache, lower abdominal pain or cramps, rash and chill or shivering.
They usually occur within the first two hours after administration of misoprostol and, except for
pain, are of low intensity. Side-effects will be recorded on the CRFs.
3.4.2
Adverse events
Adverse events
An adverse event is any untoward medical occurrence in a study subject administered a
pharmaceutical product. It does not necessarily have a causal relationship with this treatment. An
adverse event can therefore be any unfavourable and unintended sign, symptom, or disease
temporally associated with the use of a medicinal (investigational) product, whether or not related
to the medicinal (investigational) product.
Serious adverse events
A serious adverse event is any untoward medical occurrence that:
- results in death
- is life-threatening
- requires in-patient hospitalization or prolongation of existing hospitalization
- results in persistent or significant disability/incapacity
- results in a congenital anomaly/birth defect
Generally, inpatient hospitalization must include an overnight admission. Pre-planned elective
procedures are not to be reported as serious adverse events.
In this study continuing of pregnancy is not recorded as adverse event. It is considered as a lack
of efficacy of the investigational product.
3.4.3
Procedures for reporting and recording adverse events
The study subject will be given the opportunity to report adverse events spontaneously. A general
prompt will also be given to detect adverse events. “Did you notice anything unusual about your
health since last visit?
All adverse events will be recorded using a standard adverse event form. In case of serious
adverse events, the serious adverse event form will be used. The investigator will complete the
initial report as soon as she/he receives the first information about the serious adverse event. The
investigator forwards the serious adverse event form to Concept Foundation, Geneva by fax (attn:
Peter Hall, +41-21-801 0109 and a scanned form to Helena von Hertzen
([email protected]). A serious adverse event will be followed up until it
has resolved; has a stable level of sequelae; or the investigator no longer feels it is clinically
significant.
Concept Foundation and the Principal Investigator will communicate safety information to the
Finnish Drug Regulatory Agency, NAM, according to applicable regulatory requirements.
3.5
Study management and administration
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3.5.1 Compliance with good clinical practice (GCP) and good laboratory practice (GLP)
The study has been designed to comply with the European Medicines Agency “Note for Guidance
on Good Clinical Practice”, CPMP/ICH/135/95, July 2002. Standard operating procedures (SOPs)
have been developed and arrangements made for their implementation to ensure that the study is
conducted and that data are generated, documented (recorded), and reported in compliance with
the protocol, GCP, and the applicable regulatory requirements.
Similarly, the laboratory analyses to be undertaken in the study will comply with Directive
2004/10/EC of the European Parliament and of the Council of 11 February 2004 on the inspection
and verification of good laboratory practice (GLP).
3.5.2
Monitoring
The monitoring of the study is the responsibility of Concept Foundation. The monitor (person
responsible for monitoring) will assist the Principal Investigator with the practical conduct of the
study and assist her/him in working according to the protocol, GCP and regulatory requirements.
The Principal Investigator will allow the sponsor or its representative to periodically monitor at
mutually convenient times during and after the study.
3.5.3
Audit and inspection
The Principal Investigator will permit study-related audits by auditors mandated by Concept
Foundation and inspections by domestic regulatory authorities, given reasonable notice. The main
purposes of an audit or inspection are to confirm that the rights and well-being of the study
subjects enrolled have been protected, and that all data relevant for evaluation of the
investigational product have been processed and reported in compliance with the planned
arrangements, GCP and applicable regulatory requirements. The investigator will provide direct
access to all study documents.
3.5.4
Case Report Forms (CRF)
The CRF is essentially a data entry form but will also constitute the original (source data) medical
record as documented before the start of the study.
3.5.5
Investigator site file
The content of the investigator site file has been structured in a manner that facilitates filing,
retrieval, and/or auditing of study-related documents.
3.5.6
Product handling and accountability
The Head Pharmacist is responsible for receiving the study drugs at the Helsinki University
Central Hospital pharmacy. The study drugs will be delivered via courier from Finnish drug
wholesalers (Mifegyne®, Exelgyn and Cytotec®, Pfizer) and from Medikalla Oy - MediPharmia
(generic mifepristone and misoprostol, Medabon®, Sun Pharma). The Head Pharmacist, Helsinki
University Central Hospital will check the condition of the delivery and confirm its arrival and
condition as requested by the supplier. If there is a problem with the delivered product, the
supplier will be contacted for further instructions.
The study drugs will be stored at the clinical trials unit in the Helsinki University Central Hospital
pharmacy. The drugs will be stored at room temperature (<25°C) in a locked cabinet. The
temperature is measured every 15 minutes by a calibrated electronic recorder and monitored
daily. If the temperature increases above 25°C for more than 24h, Concept Foundation will be
contacted for further instructions.
The study drugs will be packed and labelled in the pharmacy in conformance with international
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standards and according to a random table generated by the Head Pharmacist.
The study drugs will be ordered from the ward by the study nurse via fax. These orders are to be
signed by the principal investigator or, in his absence, the assistant investigator. The Head
Pharmacist will pack the required order in a labelled paper bag, which will be sent from the
pharmacy by car to the ward. Car deliveries are made routinely twice a week.
On the ward, the study drugs will be stored in a locked cabinet reserved solely for them. The
drugs will be stored at <25°C and the temperature monitored daily by the study nurse. The study
nurse will record the receipt of the drugs on the Drug Accountability Form, as well as removal for
administration to the study subjects. On completion of the study all unused study drugs, as well as
empty packaging of the drugs used will be returned to the pharmacy. Any remaining drugs will be
destroyed at the pharmacy following approval by Concept Foundation.
3.5.7
Data handling
Concept Foundation will be responsible for data processing and analysis.
3.5.8
Clinical study report
A clinical study report, conforming to the relevant ICH guidelines, will be prepared by The
Concept Foundation together with the Principal Investigator.
3.6
Main problems anticipated: Nil
3.7
Links with other projects: Nil
3.8
Expected study outcome
It is expected that, following sublingual administration, the new generic misoprostol (co-packaged
with mifepristone) product will be bioequivalent to the original formulation misoprostol.
3.9
References
Ashok PW, Templeton A, Waagarachchi PT, Flett GM. (2002) Factors affecting the outcome
of early medical abortion: a review of 4132 consecutive cases. Brit J Obstet Gynaecol
109:1281-1289
El-Refaey H, Rajasekar D, Abdalla M, Calder L, Templeton A. (1995) Induction of abortion with
mifepristone (RU486) and oral or vaginal misoprostol. New Eng J Med 332:983-987
European Medicines Agency (2002). Note for guidance on the investigation of bioavailability and
bioequivalence. http://www.egagenerics.com/doc/emea_bioequiv-1401-98.pdf
Hamoda H, Ashok PW, Dow J, Flett GM, Templeton A. (2003) A pilot study of mifepristone in
combination with sublingual or vaginal misoprostol for medical termination of pregnancy up to 63
days gestation. Contraception, 68:335-8
Hamoda H, Ashok PW, Flett GM, Templeton A. (2005) A randomised controlled trial of
mifepristone in combination with misoprostol administered sublingually or vaginally for medical
abortion up to 13 weeks of gestation. Brit J Obstet Gynaecol, 112:1102-8
RCOG, Royal College of Obstetricians and Gynaecologists. (2004) The care of women requesting
induced abortion: Evidence-based guideline No7. London, RCOG Press
Tang OS, Schweer H, Seyberth NW, Lee SWH, Ho PC. (2002) Pharmacokinetics of different
routes of administration of misoprostol. Human Reprod 17:332-6
12
Tang OS, Chan CC, Ng EH, Lee SW, Ho PC. (2003) A prospective, randomized, placebocontrolled trial on the use of mifepristone with sublingual or vaginal misoprostol for medical
abortions of less than 9 weeks gestation. Human Reprod, 18:2315-2318.
World Health Organization Task Force on Post-ovulatory Methods for Fertility Regulation (1993).
Termination of pregnancy with reduced doses of mifepristone (RU486) in late first trimester
abortion. Contraception 50:461-475
World Health Organization Task Force on Post-ovulatory Methods for Fertility Regulation (2000).
Comparison of two doses of mifepristone in combination misoprostol for early medical abortion; a
randomized trial. Brit J Obstet Gynaecol 107:524-530
World Health Organization Task Force on Post-ovulatory Methods for Fertility Regulation (2003)
WHO multinational study of three misoprostol regimens after mifepristone for early medical
abortion. I: Efficacy. Brit J Obstet Gynaecol 110:808-818
Yu Zou, Xiaoyan Chen, Bo Song, Dafang Zhong (2007). Determination of misoprostol acid in
human plasma by liquid chromatography coupled to tandem mass spectrometry. J Chromatog B,
in press (Available online 13 January 2007)
13
Form 4.
Ethical considerations
Note: Start on this page and continue additional sheets as necessary.
4.
Ethical considerations
Approvals will be obtained from the Ethics Committee of Gynaecology and Obstetrics,
Otology, Ophtalmology, Neurology and Neurosurgery of the Hospital District of Helsinki
and Uusimaa; and from the Finnish National Agency for Medicines. The study will be
performed according to the Declaration of Helsinki.
4.1
Informed consent and confidentiality
All potential volunteers will be informed about the aims and protocol of the study, the sideeffects that may occur as a result of the treatment. The measures taken to ensure
confidentiality and their right to withdraw from the study at any time without prejudice to
their further medical care will also be explained to them. Women participating in the study
will be asked to sign the consent form.
4.2
Risk-benefit assessment
Experience gained so far with the use of mifepristone followed by misoprostol for the
termination of early pregnancy indicates that the therapy has side effects and a frequency
of short-term complications comparable to those observed after vacuum aspiration. The
most common complaint during treatment is lower abdominal pain, which results from
uterine contractions and the abortion process itself – this is felt by practically all women.
Using misoprostol, pregnancy-related symptoms, such as breast tenderness, nausea and
vomiting decrease significantly during treatment and some women experience diarrhoea or
shivering/fever during treatment. Less frequent side effects include dizziness, headache
and rash. Side effects usually occur within the first two hours after misoprostol and are of
low intensity, except for pain, which requires treatment in about half the cases.
Subjects will be informed about possible complications and qualified personnel and
facilities will be available at all times to deal with them.
Most women participating in the study can be expected to have a complete abortion and
therefore will not be exposed to risks associated with vacuum aspiration, particularly the
risks of physical trauma (cervical laceration, uterine perforation, etc). Even if surgical
intervention is required in a small number of subjects, it is likely to be easier since the
treatment will have dilated and softened the cervical canal.
No financial incentives will be offered to potential study participants and no financial
remuneration will be given to women recruited into the study, other than reimbursement of
expenses incurred as a result of participating in the study (travel expenses for extra
hospital visits; lost days of work; and outpatient clinic fees). The subjects will be provided
with a clinical follow-up, 2-3 weeks after the abortion.
14
Form 4b.
Gender issues
Note: Ensure all information requested in the corresponding section of Part 1 is provided
1.
Describe how the research addresses a demonstrated public health need and a need
expressed by women or men.
Evidence that the new product is bioequivalent to the original products used for medical
abortion is essential to ensure its availability to many women as a choice of method of
abortion. Sublingual administration of misoprostol will provide an alternative choice to
women who do wish to undergo vaginal insertion of the tablets. This maybe a more
acceptable option to some women. Furthermore, the availability of the two products in the
most commonly use effective dose provided with appropriate information, will give
additional reassurance that the drugs are provided by the physician at the correct dosage
and at the right time.
2.
How will the research reduce (or not increase) inequities in health and health care and
inequities between women and men?
Poorer women will have access to choice in methods of abortion, something that in many
countries is only available to women who can afford private services.
3.
Describe plans for disseminating results and sharing knowledge with research subjects
and the non-scientific community.
The results of the research will be communicated to the research subjects once the study
is completed. They will be also communicated to the research community via scientific
publication(s).
4.
What is the sex composition of the research team? Describe whether the research topic
warrants female or male researchers specifically.
The principal investigator is male; the co-investigator and the research nurses are female.
The research project does not warrant female or male researchers specifically.
(Use extra pages, as necessary)
15
Form 5
Budget Summary and Timeline
5a Budget
HUCH, Helsinki
Staff and study costs
CRO monitoring costs
GCP reinspection
Team meetings
Total
AAI, Ulm
Misoprostol assays
- validation
- sample analysis
Total
€73,705
€12,000
US$113,500
US$18,500
US$3,000
US$5,000
US$140,000
€18,200
€50,400
€68,600
US$28,000
US$77,400
US$105,400
PK and clinical data analysis
US$42,000
Study total
US$287,400
5b Timeline
2008
Fall
NAM
Discussions
Approval
2009
Jan Feb
Apr
May
Jun
Jul
X
X
X
Fall
X
X
Clinical
Research nurse
Research nurse 2
Start recruitment
X
X
GCP reinspection?
Data entry
Monitoring visits
Laboratory
Samples to AAI
Revalidate assay
Misoprostol assay
Meetings
Team meetings
Analysis
PK analysis
Mar
X
X
X
X
X
X
X
X
X
X
X
X
X
(Use extra pages, as necessary)
16
5c Budget justification
Briefly relate each item in the budget (personnel, supplies, subject costs, equipment, animals, etc.) to
the activities outlined in the research proposal
Senior Research Nurse
A full-time research nurse is required for 6 months, to act as the main co-ordinator on a day-to-day
basis under the direct supervision of the investigator. The nurse will be responsible for the
recruitment of women, administration of mifepristone orally and of sublingual misoprostol. She will be
responsible for blood sampling according to the schedule. She will also be responsible for the data
entry.
Research Nurse
Because of the intensive blood sampling schedule, a single research nurse can undertake the
recruitment of two subjects a week. The recruitment of a part-time (50%) research nurse will allow
this to be increased to three subjects a week. The nurse will be responsible to the senior research
nurse and will provide any necessary support for the recruitment of women, administration of drugs,
blood sampling and data entry.
Misoprostol acid assay
The serum samples will now be sent to AAI Pharma GmbH & Co. KG laboratories (Neu-Ulm,
Germany) for the assay of misoprostol acid. AAI Pharma GmbH & Co. KG laboratories is a GLPaccredited laboratory, and they are responsible for the establishment and validation of a modern
LC/MS/MS assay for misoprostol acid and the subsequent analyses of samples from the study.
17
Form 6.
Other support for the proposed research
(a) Is this research currently being supported directly by any other body?
Yes.
If yes, give the name(s) of the Organization(s), nature, amount, and duration of support being
provided
Concept will also be responsible for funding independent audit of good clinical practice (GCP) and of
good laboratory practice (GLP) by South Barn Consultants Ltd, UK; and study monitoring and quality
assessment by Medfiles, Medikalla OY, Finland; It will also be responsible for the validation of the
misoprostol acid assay and the analyses of misoprostol acid by AAI Pharma GmbH & Co. KG.
(b) Is this application currently being considered elsewhere?
No.
18
Form 7.
Curricula vitae of the principal investigator(s) and co-investigator(s)
(Other formats containing the same information are acceptable.)
Please provide one form for each scientist involved in the project.
Mikko A. Oskari Heikinheimo
Birth
Current position
Training
1989
1990
1992-1994
1996
2000
2006
2007
11.1.1963, Jyväskylä, FINLAND
Associate professor / Dept of Ob&Gyn, University of Helsinki
Senior physician / Hospital district of Helsinki and Uusimaa (HUS)
Senior lecturer (Ob&Gyn) / University of Helsinki
University of Helsinki
Jones Institute, EVMS, Norfolk, VA
Elected and additional positions
1997-2004
Director
1998-2000
1998 ->
1999-2000
1999-2002
2000-2005
2002-2005
2002-2004
2003 ->
Secretary
Private physician
Editor
Consultant
Secretary
Treasurer
Board member
Member
2004 ->
2004 ->
2005 ->
Member
Council member
Chairman
Medical doctor
Doctor of medicine and surgery (PhD)
Research fellow / Reproductive endocrinology
Senior lecturer (endocrinology)
Specialist in obstetrics and gynecology
Acting professor (obstetrics and gynecology)
Senior lecturer (obstetrics and gynecology)
Steroid Research Laboratory/Dept of
Biomedicine/University of Helsinki
Promotion 2000 -committee/Univ of Helsinki
Femeda clinic
Duodecim/specialist news
Schering Oy
Ethics committee/Ob&Gyn/HUS
The Finnish Menopause Society
Duodecim - scholarship foundation
International asoprisnil advisory board /
Schering Ag
Advisory board / Schering Finland Oy
Duodecim
Termination of pregnancy - committee for
national guidelines
69 peer reviewed articles
35 editorials, reviews or chapters
Publications
Research grants (>10.000 €)
1992
Sigrid Jusélius foundation – fellowship-grant
1993
Sigrid Jusélius foundation – fellowship-grant
1998
EVO-research grant/HUS
2002-2004
Finnish Medical Foundation – clinical investigator’s grant
2002
2003
2007
2008
Awards
155.000 Fmk
200.000 Fmk
100.000 Fmk
150.000 €
38.000 €
41.000 €
45.000 €
50.000 €
Seth Wichmann award / Finnish society of obstetrics and gynecology, 2000
19
Official opponent
Riitta Koivunen, M.D. / University of Oulu, 24.8.2001
Dr. José Inzunza / Karolinska Institutet, Stockholm, 28.5.2003
Dr. Jennifer E. Scott / Karolinska Institutet, Stockholm, 7.4.2004
Tiina Backman, M.D. / University of Turku, 23.3.2007
Thesis reviewer
Annaleena Heikkilä, M.D. / University of Kuopio, 23.5.2003
Sirpa Hirvonen-Santti, M.D. / University of Helsinki, 10.12.2003
Marjut Otala, Ph.D. / University Helsinki, 17.12.2004
Med Dr. Christian Fiala / Karolinska Institutet, Stockholm, 7.10.2005
Stefan Karlsson, Ph.D. / Åbo Academi, Turku, 12.6.2006
Thesis supervisions
Helena Honkanen, M.D. / University of Helsinki, 16.1.2004
’Medical abortion’
Päivi Lehtovirta, M.D. / University of Helsinki, 12.10.2007
‘HIV in Ob&Gyn’
Selected publications 1996-2007
Heikinheimo O, Gordon K, Williams R, Hodgen G. Inhibition of ovulation by progestin analogs (agonists vs
antagonists): preliminary evidence for different sites and mechanisms of actions. Contraception, 1996; 53: 5564.
Heikinheimo O, Hsiu JG, Gordon K, Kim S, Williams R, Gibbons W, Hodgen G. Endometrial effects of RU486 antiproliferative effects despite signs of estrogen action and increased cyclin-B expression. J Steroid Biochem
Mol Biol, 1996; 59: 179-190.
Greb R, Heikinheimo O, Williams R, Hodgen G, Goodman A. Vascular endothelial growth factor (VEGF) in
primate endometrium is regulated by estrogen-receptor and progesterone-receptor ligands in vivo. Human
Reproduction, 1997; 12: 1280-1292.
Heikinheimo O, Ranta S, Moo-Young A, Lähteenmäki P, Gordon K. Parenteral administration of progestin
Nestorone® to lactating cynomolgus monkeys: an ideal hormonal contraceptive at lactation? Human
Reproduction, 1999; 14: 1993-1997.
Hashiba Y, Asada Y, Heikinheimo O, Lanzendorf S, Mizutani S. Microinjection of antisense c-mos
oligonucleotides prevents the progression of meiosis in human and hamster oocytes. Fertility and Sterility,
2001; 76: 143-147.
Honkanen H, Ranta S, Ylikorkala O, Heikinheimo O. The kinetics of serum hCG and progesterone in response
to oral and vaginal administration of misoprostol during medical termination of early pregnancy. Human
Reproduction, 2002; 17: 2315-2319.
Heikinheimo O, Raivio T, Honkanen H, Ranta S, Jänne OA. Termination of pregnancy with mifepristone and
prostaglandin suppresses transiently circulating glucocorticoid bioactivity. J Clin Endocrinol Metab, 2003;88:
323-326.
Honkanen H, Rutanen E-M, Heikinheimo O. Differential kinetics of serum and cervical insulin-like growth factorbinding protein-1 during mifepristone-misoprostol-induced medical termination of early pregnancy. Molecular
Human Reproduction, 2004; 10: 65-70.
Leminen R, Raivio T, Ranta S, Oehler J, von Hertzen H, Jänne AO, Heikinheimo O. Late follicular phase
administration of mifepristone suppresses circulating leptin and follicle-stimulating hormone – mechanism(s) of
action in emergency contraception? European Journal of Endocrinology, 2005; 152: 411-418.
Heikinheimo O, Leminen R, Raivio T. Mifepristone in inhibition of the midcycle gonadotropin surge – evidence
for both ovarian and pituitary sites of action. Fertility and Sterility, 2005, 84: 1545-1546.
Heikinheimo O, Lehtovirta P, Suni J, Paavonen J. The levonorgestrel-releasing intrauterine system (LNG-IUS)
in HIV-infected women – effects on bleeding patterns, ovarian function and genital shedding of HIV. Human
Reproduction, 2006; 21: 2857-2861.
20

Form 1. Particulars of the project and investigator(s)

Transcription

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