Achondroplasia
Conditions
Keywords
Achondroplasia, Dwarfism
Brief summary
The trial is a multicenter, double-blind, randomized, placebo-controlled, dose escalation trial of weekly TransCon CNP administered subcutaneously in prepubertal children 2 to 10 years old, inclusive, with Achondroplasia.
Interventions
DRUGTransCon CNP
TransCon CNP drug product is a lyophilized powder in a single-use vial containing either TransCon CNP 3.9 mg CNP-38/vial or TransCon CNP 0.80 mg CNP-38/vial. Prior to use, the lyophilized powder is reconstituted with sterile water for injection and administered by subcutaneous injection via syringe and needle.
Weekly subcutaneously injection of placebo.
Sponsors
Ascendis Pharma A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
There are 5 cohorts enrolling approximately 60 subjects who will be randomized to receive either TransCon CNP or Placebo in a 3:1 ratio
Eligibility
Sex/Gender
ALL
Age
2 Years to 10 Years
Healthy volunteers
No
Inclusion criteria
1. Clinical diagnosis of ACH with genetic confirmation 2. Age between 2 to 10 years old (inclusive) at Screening Visit 3. Prepubertal (Stage 1 breasts for girls or testicular volume \< 4ml for boys) at Screening Visit 4. Able to stand without assistance 5. Caregiver willing and able to administer subcutaneous injections of study drug
Exclusion criteria
1. Clinically significant findings at Screening that: * are expected to require surgical intervention during participation in the trial or * are musculoskeletal in nature, such as Salter-Harris fractures and severe hip pain or * otherwise are considered by investigator or Medical Monitor/Medical Expert to make a participant unfit to receive study drug or undergo trial related procedures 2. Have received treatment (\>3 months) of human growth hormone (hGH) or other medications known to affect stature or body proportionality at any time 3. Have received any dose of medications intended to affect stature or body proportionality within the previous 6 months of Screening Visit 4. Have received any study drug or device intended to affect stature or body proportionality at any time 5. History or presence of injury or disease of the growth plate(s), other than Achondroplasia, that affects growth potential of long bones
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Height Velocity (cm/Year) After 52 Weeks of Double-blind Treatment | 52 weeks | The primary efficacy analysis compared the difference in the primary efficacy endpoint between the TransCon CNP treatment group and the pooled placebo group using an ANCOVA model with the annualized height velocity (AHV) at Week 52 as the response variable, treatment (dose groups and placebo) and sex as factors, baseline age and baseline height SDS as the covariates, and based on the Full Analysis Set. |
Countries
Australia, Austria, Denmark, Germany, Ireland, New Zealand, Portugal, United States
Contacts
STUDY_DIRECTORStudy Director, MD
Ascendis Pharma, Inc.
Participant flow
Pre-assignment details
A total of 60 participants were screened and 57 participants met eligibility criteria and were enrolled into the trial and randomized in the planned ratio of approximately 3:1 (TransCon CNP: Placebo) within sequential dose escalation cohorts. All 57 participants completed the 52-week double-blind period & entered the 104-week open-label extension (OLE) period, where they received TransCon CNP. All participants received up to a maximum of 100-mcg dose of TransCon CNP during the OLE period.
Participants by arm
| Arm | Count |
|---|---|
| TransCon CNP 6 mcg TransCon CNP 6 mcg CNP/kg delivered once weekly by subcutaneous injection.
TransCon CNP: TransCon CNP drug product is a lyophilized powder in a single-use vial containing either TransCon CNP 3.9 mg CNP-38/vial or TransCon CNP 0.80 mg CNP-38/vial. Prior to use, the lyophilized powder is reconstituted with sterile water for injection and administered by subcutaneous injection via syringe and needle. | 10 |
| TransCon CNP 20 mcg TransCon CNP 20 mcg CNP/kg delivered once weekly by subcutaneous injection.
TransCon CNP: TransCon CNP drug product is a lyophilized powder in a single-use vial containing either TransCon CNP 3.9 mg CNP-38/vial or TransCon CNP 0.80 mg CNP-38/vial. Prior to use, the lyophilized powder is reconstituted with sterile water for injection and administered by subcutaneous injection via syringe and needle. | 11 |
| TransCon CNP 50 mcg TransCon CNP 50 mcg CNP/kg delivered once weekly by subcutaneous injection.
TransCon CNP: TransCon CNP drug product is a lyophilized powder in a single-use vial containing either TransCon CNP 3.9 mg CNP-38/vial or TransCon CNP 0.80 mg CNP-38/vial. Prior to use, the lyophilized powder is reconstituted with sterile water for injection and administered by subcutaneous injection via syringe and needle. | 10 |
| TransCon CNP 100 mcg TransCon CNP 100 mcg CNP/kg delivered once weekly by subcutaneous injection.
TransCon CNP: TransCon CNP drug product is a lyophilized powder in a single-use vial containing either TransCon CNP 3.9 mg CNP-38/vial or TransCon CNP 0.80 mg CNP-38/vial. Prior to use, the lyophilized powder is reconstituted with sterile water for injection and administered by subcutaneous injection via syringe and needle. | 11 |
| Placebo Placebo mimicking 6, 20, 50, or 100 mcg CNP/kg delivered once weekly by subcutaneous injection.
Placebo for TransCon CNP: Weekly subcutaneously injection of placebo. | 15 |
| Total | 57 |
Baseline characteristics
| Characteristic | TransCon CNP 6 mcg | TransCon CNP 20 mcg | TransCon CNP 50 mcg | TransCon CNP 100 mcg | Placebo | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 6.52 years STANDARD_DEVIATION 2.593 | 6.29 years STANDARD_DEVIATION 2.896 | 5.20 years STANDARD_DEVIATION 2.991 | 5.79 years STANDARD_DEVIATION 2.613 | 5.89 years STANDARD_DEVIATION 3.109 | 5.94 years STANDARD_DEVIATION 2.8 |
| Body Mass Index (BMI) | 21.10 kg/m^2 STANDARD_DEVIATION 1.664 | 22.52 kg/m^2 STANDARD_DEVIATION 2.599 | 20.61 kg/m^2 STANDARD_DEVIATION 1.496 | 21.11 kg/m^2 STANDARD_DEVIATION 1.612 | 21.39 kg/m^2 STANDARD_DEVIATION 1.853 | 21.36 kg/m^2 STANDARD_DEVIATION 1.93 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 2 Participants | 2 Participants | 1 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 11 Participants | 6 Participants | 9 Participants | 14 Participants | 49 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Height | 90.63 cm STANDARD_DEVIATION 8.973 | 92.29 cm STANDARD_DEVIATION 12.103 | 86.61 cm STANDARD_DEVIATION 12.967 | 89.23 cm STANDARD_DEVIATION 12.822 | 90.85 cm STANDARD_DEVIATION 14.92 | 90.03 cm STANDARD_DEVIATION 12.434 |
| Height SDS | -5.45 standard deviation score STANDARD_DEVIATION 1.046 | -4.87 standard deviation score STANDARD_DEVIATION 0.673 | -4.85 standard deviation score STANDARD_DEVIATION 0.801 | -4.92 standard deviation score STANDARD_DEVIATION 0.829 | -4.85 standard deviation score STANDARD_DEVIATION 0.958 | -4.97 standard deviation score STANDARD_DEVIATION 0.873 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 10 Participants | 8 Participants | 10 Participants | 12 Participants | 48 Participants |
| Sex: Female, Male Female | 7 Participants | 3 Participants | 3 Participants | 6 Participants | 5 Participants | 24 Participants |
| Sex: Female, Male Male | 3 Participants | 8 Participants | 7 Participants | 5 Participants | 10 Participants | 33 Participants |
| Weight | 17.49 kg STANDARD_DEVIATION 3.677 | 19.67 kg STANDARD_DEVIATION 6.602 | 15.67 kg STANDARD_DEVIATION 4.399 | 17.03 kg STANDARD_DEVIATION 4.699 | 17.99 kg STANDARD_DEVIATION 5.542 | 17.64 kg STANDARD_DEVIATION 5.129 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 11 | 0 / 10 | 0 / 11 | 0 / 15 | 0 / 57 |
| other Total, other adverse events | 9 / 10 | 11 / 11 | 10 / 10 | 10 / 11 | 14 / 15 | 57 / 57 |
| serious Total, serious adverse events | 1 / 10 | 0 / 11 | 1 / 10 | 0 / 11 | 0 / 15 | 2 / 57 |
Outcome results
Primary
Annualized Height Velocity (cm/Year) After 52 Weeks of Double-blind Treatment
The primary efficacy analysis compared the difference in the primary efficacy endpoint between the TransCon CNP treatment group and the pooled placebo group using an ANCOVA model with the annualized height velocity (AHV) at Week 52 as the response variable, treatment (dose groups and placebo) and sex as factors, baseline age and baseline height SDS as the covariates, and based on the Full Analysis Set.
Time frame: 52 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| TransCon CNP 6 mcg | Annualized Height Velocity (cm/Year) After 52 Weeks of Double-blind Treatment | 4.09 cm/year |
| TransCon CNP 20 mcg | Annualized Height Velocity (cm/Year) After 52 Weeks of Double-blind Treatment | 4.52 cm/year |
| TransCon CNP 50 mcg | Annualized Height Velocity (cm/Year) After 52 Weeks of Double-blind Treatment | 5.16 cm/year |
| TransCon CNP 100 mcg | Annualized Height Velocity (cm/Year) After 52 Weeks of Double-blind Treatment | 5.42 cm/year |
| Placebo | Annualized Height Velocity (cm/Year) After 52 Weeks of Double-blind Treatment | 4.35 cm/year |
Comparison: ANCOVA model using treatment (dose groups and pooled placebo) and sex as fixed effects, and baseline age and baseline height SDS as the covariates.p-value: =0.6004ANCOVA
Comparison: ANCOVA model using treatment (dose groups and pooled placebo) and sex as fixed effects, and baseline age and baseline height SDS as the covariates.p-value: =0.7022ANCOVA
Comparison: ANCOVA model using treatment (dose groups and pooled placebo) and sex as fixed effects, and baseline age and baseline height SDS as the covariates.p-value: =0.0849ANCOVA
Comparison: ANCOVA model using treatment (dose groups and pooled placebo) and sex as fixed effects, and baseline age and baseline height SDS as the covariates.p-value: =0.0218ANCOVA