Clinical trials: optimal use of new and existing medications or Are

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Once-weekly Isoniazid and
Rifapentine for Treating TB Infection
Bob Belknap MD
Director, Denver Metro TB Program
President, NTCA
© 2014 Denver Public Health
Disclosures
• No financial disclosures
Session Objectives
Participants will be able to describe:
• The efficacy and safety of 3HP when given by
directly-observed therapy (DOT)
• The adherence to 3HP by self-administered therapy
(SAT) compared to DOT in the TBTC I-Adhere Study.
• Recommendations for educating and monitoring
patients to maximize adherence and minimize the
risks of adverse drug reactions.
Prevent TB – TBTC Study 26
Treatment Completion:
82% with 3HP
69% with 9H
Sterling NEJM December 2011
HIV-infected – South Africa
Martinson NEJM July 2011
HIV-infected – Study 26
Sterling CROI 2014, poster 586
Children Age 2-17: Study 26
Villarino JAMA Peds 2015
Pre-transplant Patients
• 17 patients awaiting solid organ transplant
– 8 kidney, 7 liver, 2 heart
– 14 foreign-born
• 13 (76%) completed treatment
• 4 underwent transplant
• No cases of active TB during follow-up
Lopez de Castilla Transplantation Jan 2014
Prevent TB – TBTC Study 26
Sterling NEJM December 2011
HIV-infected – South Africa
Grade 3/4 AST or ALT
3HP
1.5%
3HR
2.4%
Cont H
28.0%
6H
5.5%
HIV-infected – Study 26
Sterling CROI 2014, poster 586
Children Age 2-17: Study 26
Grade 3 AE:
3HP – 1 influenza-like illness, 2 rash
9H – 1 hepatomegaly and rash
Villarino JAMA Peds 2015
Pre-transplant Patients
Lopez de Castilla Transplantation Jan 2014
Post-marketing Study
•
Observational cohort
• 16 sites
• 7/1/11 – 12/31/13
• 3,346 started treatment
–
•
39 became ineligibile
3,307 eligible to
complete
Treatment Completion by Site
120
3,307 Eligible
• 2,884 (87%) completed
– 247 (7.5%) symptoms
– 176 (5.3%) other reason
Treatment Completion Rate (%)
• 423 (13%) stopped
100
88
8
83 84 85 85 87 88
1
Min= 81
Max= 100
Range= 19
Median= 89
Std. Dev.= 5 95
90 91 91 91 92
Variance= 25
97
1
80
60
40
20
0
L
E
J
A
F
D
I
N
K
H
O
Participating Site
* Each treatment completion rate represents the proportion of those completing treatment among
those eligible to complete treatment at that site
P
C
B
G
M
Symptoms and Treatment Outcomes
600
15%
500
400
300
12%
8%
8%
7%
6%
200
6%
6%
5%
4%
4%
4%
100
0.7%
0
Completed Tx
*Patients can have more than one symptom
Discontinued Tx
Post-marketing Study
•
•
•
•
1,131 (36.5%) of patients reported at least on symptom
Of these, 848 (75%) completed treatment
Odds ratio (OR) for stopping treatment was 4.9 (3.9, 6.0) for
those reporting at least one symptom between doses 1-10
Nausea/vomiting was the most common symptom (1,033
reports in 498 people)
• OR of 2.6 (1.5,4.3) for stopping treatment
• OR of 0.4 (0.2, 0.7) if isolated nausea
•
•
23 (0.07%) seen in ED or hospitalized
No deaths or permanent organ damage reported
Conclusions
• High treatment completion rate, 87.2% , even in difficult to treat
populations
• Being ≥65 years old, in correctional facilities, homeless, or eversmokers were associated with treatment discontinuation
• Being a student, recent contact, or younger was associated with
treatment completion
• ~one-third of patients reported symptoms while on the regimen
but 75% went onto complete treatment
• Reporting symptoms increased the odds of stopping treatment by
4.9
• Isolated nausea was not associated with treatment discontinuation
• No permanent negative sequelae
I-Adhere: TBTC Study 33
Shepardson IJTLD Dec 2013, update 2014
http://www.mtholyoke.edu/~dshepard/LTBI/LTBI-cost-effectiveness.zip.
I-Adhere: TBTC Study 33
Background and Rationale:
– The cost and logistics of DOT have limited
the programmatic use of 3HP
– Patients don’t like DOT (affects acceptance)
– Adherence to SAT is unknown (but assumed
to be < DOT)
– SAT completion could be lower than DOT
and still be cost effective
Short Messaging Service (SMS)
• SMS/text reminders have been used
successfully to improve adherence to medical
therapy:
– Vaccine utilization, medications (HIV and asthma),
access to care, and follow-up
• Access to cellular phones is widespread and
increasing
• SMS access among LTBI patients and impact
on treatment completion are unknown
Prev Med ‘04 38(4):503; Lancet ‘10 376:1838; Respir Med ’10 104(2):166
I-Adhere - Protocol Synopsis
• Phase IV open label, randomized design
• Target Population: adults with LTBI
• All patients received 3HP
1. DOT (control)
2. Standard SAT
3. SAT with weekly SMS reminders
• Sample size to detect a difference in study arms of
15% or greater based on cost modelling
• Enrollment targeted > 75% from U.S.
I-Adhere: Objectives
Primary:
Treatment completion by DOT vs SAT with or
without SMS reminders
Secondary:
– Determine the availability, acceptability and
impact of using weekly SMS reminders
– Monitor for toxicity, active TB, and drug resistance
– Measure patient costs associated with treatment
– Evaluate the characteristics and patterns of
adherence among SAT patients
I-Adhere: Inclusion
• Males and non-pregnant, non-nursing females
• Age > 18
• Weight > 45 kg & can get RPT 900mg and INH 900mg
weekly (no option for dose adjustment)
• Any clinical indication for LTBI
– (+) TST or IGRA in close contacts to active TB, HIV-infected,
parenchymal fibrosis, converters, recent immigrants etc.
– (-) TST or IGRA but recommended for LTBI (eg. HIV-infected
close contacts to active TB)
I-Adhere: Exclusion
•
•
•
•
Confirmed or suspected active TB
Contacts to cases with INH or Rif resistance
> 1 week of treatment for active or latent TB
Anyone who is not a candidate for SAT per local
standards
• ALT > 5x ULN (if determined)
• Patients with HIV and
1. CD4 < 350 or
2. Currently taking or planning to take ARVs in the next 120
days
I-Adhere: Demographics
I-Adhere: Demographics
Individuals listed once in the order presented
I-Adhere: Completion
Differences in Completion Rates for DOT minus SAT and DOT
minus eSAT: Total and U.S. only
I-Adhere: Active TB
DOT
(n=337)
SAT
(n=337)
SAT + SMS
(n=328)
Total
3HP
(N=1002)
337
337
328
1002
Follow up (days)
105,885
97,033
98,702
301,620
Follow up (years)
294.1
269.5
274.2
837.8
TB cases (N)
0
0
1
1
TB rate (per year)
0
0
0.36 – ITT
0 – PC*
0.12
(95%CI 0.10-0.14)
Patients (N)
*TB case: White 19 year old female, HIV negative, U.S. born, white, hispanic ethnic origin,
was enrolled into eSAT. Indication for treatment of LTBI was contact with a patient diagnosed
with smear positive TB. Pregnancy was diagnosed in study participant shortly after
enrollment (pregnancy test prior to enrollment was negative).
The patient did NOT receive any doses of 3HP
I-Adhere: Adverse Events
Treatment group
DOT
SAT
N=337
N=337
n(%)*
n(%)*
n=55
n=58
SAT+SMS
N=328
n(%)*
n=62
TOTAL
3HP
N=1002
n(%)
n=175
30 (8.9)
23 (6.8)
0**
34 (10.1)
24 (7.1)
0**
32 (9.8)
28 (8.5)
1(0.3)**
96 (9.6)
75 (7.5)
1 (0.1)
No
Yes
42 (12.5)
13 (3.9)
53 (15.7)
5 (1.5)
55 (16.8)
7 (2.1)
150 (15.0)
25 (2.5)
ATTRIBUTION TO DRUGS
Definite/Probable/Possible
Unlikely/Not related/N/A
24 (7.1)
31 (9.2)
27 (8.0)
31 (9.2)
25 (7.6)
37 (11.3)
76 (7.6)
99 (9.9)
Description
Patients with events
SEVERITY GRADE
Grade I,II, N/A
Grade III, IV
Death during therapy (Grade V)
SAE
For patients with more than 1 AE, the AE was chosen in hierarchical order: severity, grade, attribution. *Percentages were made
based on the total of enrollments. ** Deaths with onset date > 45 days after treatment completion are not included.
I-Adhere: Death
Patient, 25 years old black male, unemployed, close contact
of a patient with active TB, was enrolled on into SAT+SMS
arm. At enrollment patient reported history of alcohol abuse,
but no other medical conditions (no symptoms of depression
or suicidal ideation were reported by the patient at
enrollment). Patient received one dose of 3HP therapy. Five
days after taking his first study dose, patient committed
suicide. After careful review of the event by research site’s
investigators, the event was deemed not to be related to
3HP.
I-Adhere: Signs and Symptoms
I-Adhere: Summary
• Population enrolled was more representative of
patients with LTBI (results are generalizable)
• Adherence to 3HP by DOT was higher than observed
in Study 26 (similar observation in post-marketing
study)
• Treatment completion with 3HP by SAT is
comparable to 3HP by DOT in the USA
I-Adhere: Summary
• No treatment related deaths or observed increased
toxicity in SAT arms compared to DOT
• Additional analyses:
– extended safety (including sign and symptoms
trends, Hypersensitivity, etc.)
– cost-effectiveness of 3HP SAT compared to other
LTBI regimens in the U.S.
– Exploring the role (if any) of SMS
Session Objectives
Participants will be able to describe:
• The efficacy and safety of 3HP when given by
directly-observed therapy (DOT)
• The adherence to 3HP by self-administered therapy
(SAT) compared to DOT in the TBTC I-Adhere Study.
• Recommendations for educating and monitoring
patients to maximize adherence and minimize the
risks of adverse drug reactions.
I-Adhere: Study Drugs
x4
110 mm
55 mm
223 mm
x1
Standardized Patient Education
A. How to Use Your
Medication Box
Standardized Patient Education
To open the MEMS
cap
Turn left
Push
down
Push down and
turn MEMS cap
to the left
3HP SAT - Adherence
• Observe doses in clinic when able (first dose
and at monthly follow-up)
• Prepackage the pills with clearly printed dates
for when they should be taken
• Give maximum of 4 SAT doses
• Current: 10 pills (6 rifapentine, 3 INH, 1 Vit B6)
• Future: 4 pills (3 RPT/INH + 1 B6)
+
2xPriftin® 150mg
=
Isoniazid®
PH 300/300
3HP –Education and Monitoring
• NEW - Important to educate about the possibility of
dizziness +/- hypotension
• Side effects reported more commonly in patients on
other medications
• Hepatotoxicity is less common but still important;
monitor ALT as you would with INH
• Drug-drug interactions are important to consider
• Monthly in-person monitoring for toxicity and
adherence is strongly recommended
3HP - Conclusions
• Data continues to support that 3HP is safe and
effective compared to INH
• DOT should be used in settings where the cost
and logistics make sense (schools, jails, etc.)
• Completion with 3HP SAT in adults was
comparable to historical results with rifampin and
better than INH
• Shorter-course, patient-centered therapy is
critical for expanding the scope and effectiveness
of TB prevention efforts

Clinical trials: optimal use of new and existing medications or Are

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