COACH: A Phase 2, Open-Label, Single-Arm, 156-week Trial to Investigate the Efficacy, Safety and Tolerability of Combined Once Weekly Navepegritide and Lonapegsomatropin in Children with Achondroplasia

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ascendis Pharma Growth Disorders A/S

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

Trial duration

26 Jul 2024 → ongoing

Decision date (initial)

2024-04-23

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Ascendis Pharma Growth Disorders A/S, Denmark

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To evaluate the effect of navepegritide and lonapegsomatropin on linear growth, compared to navepegritide alone and to evaluate the safety profile of navepegritide and lonapegsomatropin.

Secondary objectives 12

1. To evaluate the effect of combination therapy navepegritide and lonapegsomatropin on linear growth, compared to placebo.
2. To evaluate the effect of navepegritide and lonapegsomatropin on linear growth, compared to navepegritide alone or placebo.
3. To evaluate the effect of navepegritide and lonapegsomatropin on ACH experience measures, compared to navepegritide alone or placebo.
4. To evaluate the effect of navepegritide and lonapegsomatropin on quality of life, compared to navepegritide alone or placebo.
5. To evaluate the treatment impact of navepegritide and lonapegsomatropin on sleep, compared to navepegritide alone or placebo.
6. To evaluate the treatment impact of navepegritide and lonapegsomatropin on growth of dysplastic bone, compared to navepegritide alone or placebo
7. To evaluate the effect of navepegritide and lonapegsomatropin on body composition, compared to navepegritide alone or placebo.
8. To evaluate the treatment impact of navepegritide and lonapegsomatropin on physical functioning, compared to navepegritide alone or placebo.
9. To evaluate the safety and tolerability of navepegritide and lonapegsomatropin.
10. To characterise PK of navepegritide and lonapegsomatropin.
11. To evaluate the PD biomarkers of lonapegsomatropin.
12. To assess potential immunogenic response to navepegritide and lonapegsomatropin.

Conditions and MedDRA coding

Children with Achondroplasia

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Written, signed informed consent and/or assent (if applicable) by the parent(s) or legal representative(s) of the participant, and as required by the IRB/HREC/IEC.
2. Male or female between 2 to 11 years of age (inclusive) at the time of Visit 1.
3. Clinical diagnosis of ACH with genetic confirmation of heterozygote genotype present at Visit 1. Documentation of historic test results are acceptable for proof of diagnosis.
4. Able to stand without assistance.
5. Parent(s)/caregiver(s)/legal guardian(s) willing and able to administer weekly SC injections of IMP and comply with all protocol requirements.
6. At least 6 months of growth and disease history from TCC-NHS-01 or TCC-201 or comparable growth and disease history available from medical records.

Exclusion criteria 27

1. Participation in any interventional clinical trial within three months prior to screening (except TCC-201 or ASND0039).
2. Cervicomedullary decompression surgery within 6 months prior to Screening or with anticipated need for repeat decompression surgery during the time of the trial.
3. Evidence at screening consistent with severe cervicomedullary junction compression based on clinical and/or radiologic findings that indicate immediate surgical intervention is required.
4. Ventriculoperitoneal shunt and laminectomy with full recovery within 6 months prior to Screening.
5. Salter-Harris fracture within 6 months prior to screening (within 2 months for fracture of digits and buckle fractures).
6. Clinically significant musculoskeletal disease, such as Salter-Harris fractures or clinical and/or radiographic evidence of severe hip pathology
7. Planned or expected surgical intervention during trial participation that may significantly affect trial parameters (confounding of safety events) or would prevent the participant from performing trial procedures. Minimally invasive surgeries such as insertion of grommets, adenoidectomy, tonsillectomy, or myringotomy tube placement, are permitted during the trial.
8. Severe untreated sleep apnoea or newly initiated sleep apnoea treatment (e.g., Continuous Positive Airway Pressure [CPAP] in the previous 2 months prior to screening).
9. Clinically significant finding or arrhythmia as determined by the investigator that indicates abnormal cardiac function or conduction that includes, but is not exclusive to: a. Repaired or unrepaired coarctation. b. Moderate or greater complexity congenital heart disease including tetralogy of Fallot, Atrioventricular septal defects, truncus arteriosus, total anomalous pulmonary venous return, double outlet right ventricle, or single ventricle heart disease.
10. QT corrected using Fridericia's correction (QTcF) ≥ 450 msec at screening.
11. Known history or presence of condition that impacts haemodynamic stability (such as autonomic dysfunction and orthostatic intolerance).
12. Closed epiphysis at screening.
13. Known history or presence at screening of the following: a. Chronic anaemia (iron deficiency anaemia that is resolved or considered adequately treated in the Investigator’s opinion is allowed). b. Chronic renal insufficiency defined as estimated glomerular filtration rate (eGFR) according to the revised bedside Schwartz equation less than <60 mL/min/1.73 m2 for >3 months. c. Chronic or recurrent illness that can affect hydration or volume status, including conditions associated with decreased nutritional intake or increased volume loss. d. Acute critical illness following open heart surgery, abdominal surgery, multiple accidental trauma, acute respiratory failure or similar conditions for which lonapegsomatropin treatment is contraindicated.
14. Known history or presence of malignant disease.
15. Hepatic transaminases (aspartate aminotransferase (AST) or alanine transferase (ALT)) greater than 3x upper limit of normal (ULN) at screening.
16. Serum 25-hydroxy-vitamin D (25OHD) level of <30 nmol/L (<12 ng/mL) at screening. Participants with 25OHD levels between 30-50 nmol/L (12-20 ng/mL) may be enrolled provided treatment with Vitamin D supplementation is initiated.
17. Any disease or condition that, in the opinion of the Investigator, may make the participant unlikely to fully complete the trial, may confound interpretation of trial results, or may present undue risk from receiving trial treatment. This could include family situations, complications or manifestations, or medications that might impact safety or be considered confounding.
18. Sexually active male and female participants who are unwilling or unable to use a highly effective form of contraception for the entire trial period and for 90 days after last dose of trial treatment
19. Female participants who are pregnant, lactating or breastfeeding.
20. History of or suspected hypersensitivity to the IMP or related products.
21. Findings on fundoscopy at screening consistent with intracranial hypertension, papilledema, or evidence of any other retinal disease for which GH therapy is contraindicated.
22. Have a growth disorder or medical condition other than ACH that results in short stature or abnormal growth such as severe ACH with developmental delay and acanthosis nigricans (SADDAN), hypochondroplasia, GHD, Turner syndrome, pseudoachondroplasia, inflammatory bowel disease, celiac disease, hypothyroidism, hyperthyroidism, pre-diabetes, or diabetes mellitus.
23. Have received any dose of prescription and/or investigational medications or device intended to affect stature, growth, or body proportionality at any time prior to screening, except for those participants enrolled in Cohort B who will have prior navepegritide exposure.
24. Receiving concurrent treatment with any agent that might influence growth or interfere with GH secretion or action: a. Inhaled corticosteroid therapy at a dose of >400 µg/day of inhaled budesonide or equivalent for more than 28 consecutive days total over the course of 12 months prior to screening. b. Require, or anticipated to require, chronic (>4 weeks) or repeated treatment (more than twice/year and >3 weeks/year) with systemic corticosteroids during participation in the trial. c. Currently using or have used within 12 months prior to screening any sex steroids (for example estrogen), non-steroidal anabolic agents (for example, oxandrolone) or gonadotropin-releasing hormone (GnRH) analogues treatment. d. Treatment for attention-deficit hyperactive disorder (ADHD) such as methylphenidate.
25. Known history or presence of injury or disease of the growth plate(s), other than ACH, that affects growth potential of long bones.
26. Known history of any bone-related surgery affecting growth potential of long bones, such as Orthopaedic reconstructive surgery for bone lengthening (procedures for leg bowing such as 8-plate are not exclusionary).
27. Known or suspected intracranial pathology. Participants with a history of known intracranial pathology, such as a tumour or significant hydrocephalus, clinical resolution must be confirmed by an MRI scan at screening.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. AGV (cm/year) (Week 52).
2. TEAEs.

Secondary endpoints 12

1. AGV (cm/year) (Week 52).
2. AGV (cm/year) (Week 26, 104, 156). Change from baseline in height Z-score (Week 13, 26, 52, 104, 156).
3. Achondroplasia Child Experience Measures (Week 26, 52, 104, 156). • ACEM-OSM. ACEM-Impact. Achondroplasia Parent Experience Measure (Week 26, 52, 104, 156): APEM-Impact
4. Change from baseline in the following COAs (Week 26, 52, 104, 156). - QoLISSY. - SF-10. - PGIS. - PGIC. - HCRU. - CGI-S.
5. Change from baseline of investigator reported sleep apnoea, quality of sleep and snoring pattern (Week 26, 52, 104, 156).
6. Change from baseline in length of long bones (e.g., femur, humerus, tibia, fibula, tibia/fibula ratio), other measurements (mechanical axis lines), and vertebral column (cobb angles, vertebral posterior element morphometry, vertebral body morphometry, spinal height) using standardized radiologic assessment (Week 52, 104, 156).
7. Change from baseline in body composition including body fat, lean mass, skeletal muscle and bone mineral density using DXA assessment (Week 52, 104, 156).
8. Change from baseline in number of rises during a 1-MSTST (Week 52, 104, 156). Change from baseline in maximal knee extensor muscle strength (Week 52, 104, 156).
9. Safety assessments throughout the trial (Vital signs, ECG, safety laboratory tests, physical and skeletal examinations, injection site reactions, and fundoscopy). Bone age based on X-ray (Week 26, 52, 104 and 156).
10. Plasma concentration of Total CNP, Free CNP and mPEG. Serum concentrations of hGH and lonapegsomatropin.
11. Serum concentrations of IGF-1 and IGFBP3.
12. Detection and characterisation of both antidrug and anti-prodrug antibodies.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ascendis Pharma Growth Disorders A/S

Sponsor organisation

Ascendis Pharma Growth Disorders A/S

Address

Tuborg Boulevard 12

City

Hellerup

Postcode

2900

Country

Denmark

Scientific contact point

Organisation

Ascendis Pharma Growth Disorders A/S

Contact name

Clinical Trial Information Desk

Public contact point

Organisation

Ascendis Pharma Growth Disorders A/S

Contact name

Clinical Trial Information Desk

Third parties 17

Locations

2 EU/EEA countries · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 39 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications