# Presentation: 689681

## Meeting of the Advisory Committee for Reproductive Health DrugsAugust 29, 2006

**Barbara Wesley, M.D., M.P.H.****Division of Reproductive and Urologic Products**

## NDA 21-945 17α Hydroxyprogesterone Caproate (Gestiva)

**Proposed Indication**
- Gestiva is indicated for the prevention of preterm birth in pregnant women with a history of at least one spontaneous preterm birth
**Dosage & Administration**
- Gestiva is to be administered IM at a dose of 250 mg once a week beginning between 16-weeks 0-days (160 weeks) and 20-weeks 6-days (206 weeks) gestation to week 37 of gestation or birth

## Overview of Clinical Studies 

- Study 17P-IF-001
- Randomized, vehicle-controlled study with target enrollment of 500 subjects
- 150 subjects enrolled and treated
- Study terminated prematurely: recall of study drug
- Study 17P-CT-002
- Principal efficacy and safety study
- Terminated prematurely: crossed efficacy threshold
- 463 of 500 planned subjects enrolled and treated
- 17OHP = 310;  vehicle = 153
- Study 17P-FU
- Follow-up for long-term health and development
- 278 subjects enrolled: 17OHP = 194; vehicle = 84

## Study 17P-CT-002

- Design
- Double blind, vehicle-controlled with subjects randomized 2:1 to 17OHP or vehicle
- Inclusion Criteria
- History of spontaneous singleton preterm birth
- Gestational age of 160 to 206 at randomization
- Main Exclusion Criteria included
- Known major anomaly
- Prior progesterone or heparin Rx in current pregnancy
- Hx of thromboembolic disease
- Maternal medical/obstetrical complications including
- Current or planned cerclage
- Hypertension requiring medication
- Seizure disorder

## Study 17P-CT-002

- Study Medications
- 17α-hydroxyprogesterone caproate (250 mg/mL) in castor oil, benzyl benzoate, and benzyl alcohol
- Vehicle
- Dosing Regimen
- Weekly IM injection through Week 366 or delivery
- Primary Efficacy Endpoint
- Birth < 370 weeks
- Additional Efficacy Endpoints (post hoc)
- Birth < 350 weeks and < 320 weeks
- Composite index of neonatal morbidity
- Death, RDS, bronchopulmonary dysplasia, Gr. 3 or 4 IVH, proven sepsis, necrotizing enterocolitis

## Overview of Subject DispositionStudy 17P-CT-002

|  | 17OHP
N=310
n   (%) | Vehicle
N=153
 n    (%) |
| --- | --- | --- |
| Completed Treatment
Withdrawn from Treatment
	Due to Adverse Event
Lost to Follow-up | 	279	(90.0)
	27 	(8.7)
	6 	(1.9)
	4 	(1.3) | 	139	(91.0)
	14	(9.2)
	3	(2.0)
	0   |

## Preterm Births <370 Weeks Gestation in ITT Population (Study 17-P-CT-002) 

- PTB rate of **54.9%** in vehicle arm considerably greater than rate in other MFMU Network studies
- PTB rate of **37.1%** in 17OHP arm similar to PTB rate in control arms in another MFMU Network studies

| 17OHP
N = 310 | Vehicle
N = 153 | % Difference [Adjusted 95% Confidence Interval] |
| --- | --- | --- |
| Number (%) Preterm Births |  |  |
| 115 (37.1%) | 84 (54.9%) | -17.8% [-28%, -7%] |

**Primary Efficacy Endpoint**

## Percent of Preterm Births in Revised ITT Population (Study 17-P-CT-002)

- Confidence intervals adjusted for the interim analyses and the final analysis. To preserve overall Type I error rate of .05, p-value boundary of .035 used for the adjustment (equivalent to a 96.5% confidence interval).

| Age at  Delivery (Weeks) | 17OHP
N=310 | Vehicle
N=153 | % Difference [Adjusted 95% Confidence Interval] |
| --- | --- | --- | --- |
|  | Percent Delivered |  |  |
| < 370  | 37.1 | 54.9 | 	-17.8%	[-28%, -7.0%] |
| < 350 | 21.3 | 30.7 | 	-9.4%	 [-18.7%, -0.2%] |
| < 320 | 11.9 | 19.6 | 	-7.7%	 [-15.5%, 0.1%] |
| < 280 | 9.4 | 10.5 | 	-1.1%	[-7.4%, 5.2%] |

## Proportion of Enrolled Subjects Continuing to be Pregnant by Gestational Age

**Proportion of Enrolled Subjects Continuing to be Pregnant by Gestational Age**

## Gestational Age (Weeks) at Delivery (Study 17P-CT-002)

|  | 17OHPN=306 | VehicleN=153 |
| --- | --- | --- |
| Median | 37.5 | 36.5 |
| Mean | 36.2 | 35.2 |
| Min, Max | 18.1, 41.5 | 20.3, 41.6 |

- Difference between groups (mean)
- 	1.0 week [95%CI: 0.3,1.5]

## Birthweight (Study 17P-CT-002)

|  | 17OHP
N=301 | Vehicle
N=151 |
| --- | --- | --- |
| Mean Weight (gm) | 2760 | 2582 |
| Gm Difference [95%CI] | 178.2  [-13, 290] |  |
|  |  |  |
| Birthweight  | n     (%) | 	n    (%) |
| <2500 gm | 	82 (27.2%) | 	62 (41.1%) |
| % Difference [95%CI] | -13.8% [-23, -4.5] |  |
| <1500 gm | 	26 (8.6%) | 	21 (13.9%) |
| % Difference [95%CI] | -5.3%  [-11.6, 1.1] |  |

## Miscarriages, Stillbirths, and Neonatal Deaths (Study 17P-CT-002)

**No net survival benefit**** **

| 
Pregnancy Outcome | 17OHP
N=306
n  (%) | Vehicle
N=153
n  (%) |
| --- | --- | --- |
| Miscarriages (16 to <20 weeks)
Stillbirths
Neonatal Deaths
          Total Deaths | 	5	(1.6)
	6	(2.0)
	8	(2.6)
	19	(6.2) | 	0
	2	(1.3)
	9	(5.9)
	11	(7.2) |

## Days from Onset of Treatment to Fetal or Neonatal Death

- Days to Fetal or Neonatal Death

**50**

**100**

**150**

- 1.0

- Proportion Surviving

- 0.8

- 17OHP
- Vehicle

## Literature Reports of Fetal Loss in Women Treated with 17-hydroxyprogesterone Caproate 

**                                   **

| Study | 17OHPn  N | Vehicle
n  N |
| --- | --- | --- |
| LeVine (1964) | 3/15 | 7/15 |
| Shearman (1968) | 5/27 | 5/23 |
| Johnson (1975) | 3/23 | 0/27 |
| Yemini et al. (1985) | 8/39 | 3/40 |

- n = Number of fetal losses
- N = Number of subjects in treatment group
- From:  Keirse MJ, Brit J Obstet Gynecol 1990; 97(2):149-54

## Composite Neonatal Morbidity (Study 17P-CT-002) 

| 
Morbidity | 17OHPN=295n  (%) | VehicleN=151n  (%) |
| --- | --- | --- |
| Death (live births only) | 	8	(2.6) | 	9	(5.9) |
| Respiratory Distress Syndrome | 	29	(9.9) | 	23	(15.3) |
| Bronchopulmonary Dysplasia | 	4	(1.4) | 	5	(3.3) |
| Gr. 3/4 Intraventricular Hemorr. | 	2	(0.7) | 	0	(0.0) |
| Proven Sepsis | 	9	(3.1) | 	4	(2.6) |
| Necrotizing Enterocolitis | 	0	(0.0) | 	4	(2.7) |
| Composite Index of Morbidity* | 35 (11.9%) | 26 (17.2%) |

-  * No. subjects with one or more of the listed morbidities.

## Maternal Safety Findings (Study 17P-CT-002)

- Adverse event (AE) data not collected in usual manner
- Subjects asked if had any symptoms related to study medication
- No maternal deaths
- 3 reports of serious AEs ─ all in 17OHP group
- Pulmonary embolus 8 days post delivery
- Cellulitis at study medication injection site
- Postpartum hemorrhage, respiratory distress, endometritis
- 11 subjects discontinued because of an AE
- 7 (2.2%) in 17OHP group
- Urticaria (n=3), injection site pain/swelling (n=2) arthralgia (n=1), weight gain (n=1)
- 4 (2.6%) in control (vehicle) group
- Pruritus (n=2), injection site pain (n=1), urticaria (n=1)

## Common Adverse Events (Study 17P-CT-002)

| Preferred Term | 17OHP
N=310n    (%) | VehicleN=153n   (%) |
| --- | --- | --- |
| Injection site pain | 	108  (34.8) | 	50  (32.7) |
| Injection site swelling | 	53  (17.1) | 	12   (7.8) |
| Urticaria | 	38  (12.3) | 	17  (11.1) |
| Pruritus | 	24   (7.7) | 	9  ( 5.9) |
| Injection site pruritus | 	18   (5.8) | 	5   (3.3) |
| Nausea | 	18   (5.8) | 	7   (4.6) |
| Contusion | 	17   (5.5) | 	14   (9.2) |
| Injection site nodule | 	14   (4.5) | 	3   (2.0) |
| Vomiting | 	10   (3.2) | 	5   (3.3) |

## Selected Pregnancy Complications (Studies 17P-CT-002 and 17P-IF-001)

| Pregnancy Complication | Study | 17OHP |  |  | Vehicle |  |
| --- | --- | --- | --- | --- | --- | --- |
|  |  | 	     n |  (%) |  | n |  (%) |
| Gestational Diabetes | CT-002 | 	17 | (5.6) |  | 	7 | (4.6) |
|  | IF-001 | 	8 | (8.6) |  | 	0 | (0.0) |
| Oligohydramnios | CT-002 | 	11 | (3.6) |  | 	2 | (1.3) |
|  | IF-001 | 	2 | (2.2) |  | 	1 | (1.9) |
| Preeclampsia | CT-002 | 	27 | (8.8) |  | 	7 | (4.6) |
|  | IF-001 | 	6 | (6.5) |  | 	2 | (3.8) |

## Overview of Study 17P-IF-001

- Study Design
- Double blind, vehicle controlled, randomized 2:1
- Identical to that of Study 17P-CT-002
- Terminated prematurely: recall of study drug
- 150 subjects randomized before recall
- 104 subjects completed treatment or withdrew for reasons other than recall of study drug
- 17OHP group: 65 subjects
- Vehicle group: 39 subjects

## Key Findings from Study 17P-IF-001

**Efficacy (Subjects not affected by recall)**
- Subjects with delivery < 37 weeks
- 17OHP – 43.1% (28 of 65)
- Vehicle – 38.5% (15 of 39)
**Miscarriages, Stillbirths, and Neonatal Deaths**

| 
Pregnancy Outcome | 17OHPN=93 n  (%) | VehicleN=54n (%) |
| --- | --- | --- |
| Miscarriages (16 to <20 weeks) | 	1	(1.1) | 	1	(1.9) |
| Stillbirths | 	1	(1.1) | 	2	(3.7) |
| Neonatal Deaths | 	2	(2.2) | 	0 |
| Total Deaths | 	4	(4.4) | 	3	(5.9) |

## Overview of Study 17P-FU

- Objective
- Follow–up of children whose mothers were treated with either 17OHP or vehicle in the principal study
- Study Population
- 14 of original 19 study sites eligible to participate (children from 374 of original 463 patients - 80%)
- 278 of 374 (80%) of eligible children enrolled
- 17OHP: 194 children (82%)
- Vehicle: 84 children (74%)

## Demographics of Children in Study 17P-FU

-   Mean Gestational Ages

| Study  | Gestational Age (Weeks) |  |
| --- | --- | --- |
|  | 17OHP | Vehicle |
| 17P-CT-002 | 36.2 | 35.2 |
| 17P-FU | 37.3 | 36.2 |

|  | Months |  |
| --- | --- | --- |
|  | 17OHP | Vehicle |
| Mean | 47.2 | 48.0 |
| Range | 30.2, 63.9 | 33.5, 64.3 |

-   Age at Evaluation in Study 17P FU

## Endpoints (Study 17P-FU)

- Primary: Ages & Stages Questionnaire (ASQ)
- Communication
- Gross motor
- Fine motor
- Problem solving
- Personal/social
-    •  Positive Screen: score 2 S.D. below mean in any of 5 areas
- Secondary: Survey Questionnaire
- Activity/motor control
- Vision/hearing
- Height/weight/head circumference
- Gender specific play
- Diagnosis by a physician
- Subjects also underwent physical exam

## Number (%) of Children with ASQ Scores Suggestive of Developmental Problem

|  | 17OHP
N=193 |  | Vehicle
N=82 |  |
| --- | --- | --- | --- | --- |
| Area of Development | 	n | 	(%) | 	n | 	% |
| Communication | 	22 | (	11.4) | 	9 | 	(11.0) |
| Gross Motor | 	5 | 	(2.6) | 	3 | 	(3.7) |
| Fine Motor | 	40 | 	(20.7) | 	15 | 	(18.3) |
| Problem Solving | 	20 | (	10.4) | 	9 | 	(11.0) |
| Personal-Social | 	7 | 	(3.6) | 	1 | 	(1.2) |
|  |  |  |  |  |
| Developmental problem in one or more areas | 	53 | (27.5) | 	23 | (28.0) |

## Number (%) of Children with Low ASQ Score & Independent Diagnosis of Developmental Delay

|  |  17OHP  (N=193) |  |   Vehicle  (N=82) |  |
| --- | --- | --- | --- | --- |
|  | n |  (%) | n |  (%) |
| Total Number Affected | 13 | (6.7) | 8 | (9.8) |
|  |  |  |  |  |
| Area of Development |  |  |  |  |
| Communication | 9 | (4.7) | 7 | (8.5) |
| Gross Motor | 3 | (1.6) | 2 | (2.4) |
| Fine Motor | 10 | (5.2) | 3 | (3.6) |
| Problem Solving | 5 | (2.6) | 5 | (6.1) |
| Personal-Social | 5 | (2.6) | 1 | (1.2) |

## Summary of Issues

- Applicant is seeking approval for 17OHP based on
- Findings from a single clinical trial
- A surrogate endpoint for infant mortality/morbidity (preterm birth < 37 weeks)
- Concern about applicability to other populations
- Preterm birth rate in vehicle arm that is higher than that reported in another MFMU Network trial
- Safety concern
- Potential safety signal of increased fetal wastage in 17OHP group