E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Achondroplasia (ACH) in prepubertal children |
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E.1.1.1 | Medical condition in easily understood language |
Achondroplasia (skeletal growth disorder) in children |
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E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 25.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000452 |
E.1.2 | Term | Achondroplasia |
E.1.2 | System Organ Class | 100000004850 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
In prepubertal children with achondroplasia (ACH) at 52 weeks, • To determine the safety of once weekly subcutaneous (SC) doses of TransCon CNP • To evaluate the effect of once weekly SC doses of TransCon CNP on annualized height velocity (AHV) |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the effect of once weekly SC doses of TransCon CNP on body proportionality (upper to lower body segment ratio) in prepubertal children with ACH at 52 weeks • To evaluate the pharmacokinetic (PK) properties of once weekly SC doses of TransCon CNP • To assess the potential immunogenic response to once weekly SC doses of TransCon CNP |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 6. Written, signed informed consent of the parent(s) or legal guardian(s) of the participant and written assent of the participant as required by the institutional review board/human research ethics committee/independent ethics committee (IRB/HREC/IEC) |
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E.4 | Principal 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 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 ACH, that affects growth potential of long bones 6.History of any bone-related surgery that affects growth potential of long bones, such as orthopedic reconstructive urgery and osteotomy (Limb-lengthening with full recovery is allowed with a minimum of 12 months of bone healing). Note: Foramen magnum decompression and laminectomy with full recovery are allowed with minimum of 6 months of bone healing. History of 8 plate epiphysiodesis is allowed, but the plates must have been removed prior to Screening with minimum 4 weeks of healing. 7.Have a form of skeletal dysplasia other than ACH or known medical conditions that result in short stature or abnormal growth. 8.History or presence of malignant disease, other than basal cell epithelioma/carcinoma or completely resected squamous skin cancer with no recurrence for 12 months per medical records 9.History or presence of the following: •Chronic anemia (resolved iron deficiency anemia is allowed) •Significant cardiovascular disease per the judgement of the investigator, such as congenital heart disease (uncomplicated patent ductus arteriosus and atrial or ventricular septal defect with repair are allowed), aortic insufficiency, clinically significant arrhythmias, congestive heart failure with NYHA class II and above, or other conditions that impair regulation of blood pressure or heart rate •Condition that impacts hemodynamic stability (such as autonomic dysfunction, orthostatic intolerance) •History of chronic renal insufficiency •Chronic or recurrent illness that can affect hydration or volume status. This may include conditions associated with decreased nutritional intake or increased volume loss •Bone fracture within 6 months prior to Screening Visit (within 2 months for fracture of digits) •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 presents undue risk from receiving study drug 10.Child has significant electrocardiogram abnormalities, including evidence of a previous myocardial infarction, left ventricular hypertrophy, flat T waves (particularly in the inferior leads) or more than minor non-specific ST-T wave changes or: •QRS>90 milliseconds (msec) •QT interval corrected using Fridericia's formula (QTcF)>440 msec •PR interval>170 msec •Complete right or left bundle branch block 11.Requires, or anticipated to require, chronic (>4 weeks) or repeated (more than twice per year) treatment with oral corticosteroids during participation in the trial (low and mid-dose inhaled corticosteroids are allowed. High-dose inhaled corticosteroids are not allowed.). See Appendix 4 for definition of high doses of inhaled corticosteroids. 12.Use of medication known to prolong the QT/QTc interval within 7 days or 5 half-lives (whichever is longer) prior to the Screening Visit (see https://crediblemeds.org/ for the list of medications that are known to prolong the QT/QTc interval. Note: Only medications on the Known Risk list are excluded, not those on the Possible or Conditional Risk lists) 13.Ongoing treatment with any medication that affects blood pressure or heart rate 14.Known hypersensitivity to the components of the study drug [trehalose, tris(hydroxymethyl)aminomethane, succinate and PEG] 15.Any other reason that in the opinion of the investigator would prevent the child from complying with the trial requirements or completing the trial
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety Endpoints The following safety endpoints will be assessed for both blinded Randomised Period and Open-Label Extension Period: • Incidence of AEs • All blood chemistry, hematology, lipid panel, and urinalysis parameters • Vital sign measurements and physical examination assessments • 12-lead ECG • Radiographic findings from: - Bone age X-ray - DXA - AP standing lower extremity X-ray - AP and lateral spine X-ray • Incidence of anti-drug antibodies
Efficacy Endpoints • AHV as measured at 52 weeks of weekly TransCon CNP treatment or placebo
Pharmacokinetic Endpoints • Plasma concentration of Total CNP • Plasma concentration of Free CNP • Plasma concentration of mPEG and mPEG-linker |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Efficacy will be evaluated at 52 weeks but safety and PK will be evaluated at 52 weeks and during the open-label extension period |
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E.5.2 | Secondary end point(s) |
• Change in upper to lower body segment ratio as measured at 52 weeks of weekly TransCon CNP treatment or placebo
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
At 52 weeks of weekly TransCon CNP treatment or placebo |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 6 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 11 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Canada |
New Zealand |
United States |
Switzerland |
Austria |
Denmark |
Germany |
Ireland |
Portugal |
Spain |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 4 |