E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Hormonal diseases [C19] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10000599 |
E.1.2 | Term | Acromegaly |
E.1.2 | System Organ Class | 10014698 - Endocrine disorders |
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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 |
To evaluate the safety and tolerability of ATL1103 in patients with acromegaly.
To evaluate the single dose and multiple dose pharmacokinetic profiles of ATL1103 via the subcutaneous route in patients with acromegaly.
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E.2.2 | Secondary objectives of the trial |
To evaluate the effect of two dosing regimens of ATL1103 on serum IGF-I levels in patients with acromegaly.
To explore the effects of ATL1103 on the following parameters in patients with acromegaly:
-GH, GHBP
-IGFBP-3, ALS, IGF-II
-Ring size assessment
-Signs and Symptoms Scale
-Acromegaly Quality-of-Life questionnaire
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients who:
1. Provide written informed consent in accordance with local regulations.
2. Are 18 to 80 years of age inclusive.
3. Have acromegaly due to pituitary adenoma (micro or macro adenoma) identified by Magnetic Resonance Imaging (MRI).
4. Have serum Insulin-like growth factor-1 (IGF-1) levels at Screening >1.3 times the upper limit of normal.
5. Have nadir serum Growth Hormone (GH) levels > 1ng/mL at all test time points within the 2 hours post oral glucose load for an oral glucose tolerance test.
6. Are acromegaly treatment naïve, or who have not taken other acromegaly medications for the following periods of time prior to IGF-1 and GH Screening tests:
• Bromcriptine: 6 weeks
• Carbergoline: 8 weeks
• Quinagolide: 8 weeks
• Octreotide (subcutaneous): 4 weeks
• Pegvisomant: 8 weeks
• Octreotide LAR: 4 months
• Lanreotide (all presentations): 4 months
Note: patients on medications may washout after consenting.
7. Have a body mass index (BMI) ≥19 kg/m2.
8. Have adequate venous access to allow collection of multiple blood samples during the study.
9. Are female of non-child-bearing potential (i.e. either surgically sterilised or at least one year post-menopausal), or if of child-bearing potential, must agree to use two approved methods of contraception for the duration of the study and for three months after administration of the last dose of study drug
OR
Are male and surgically sterilized or agree to use an approved method of contraception for the duration of the study and until three months after administration of the last dose of the study medication.
10. Are willing and able to self-administer subcutaneous injections.
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E.4 | Principal exclusion criteria |
Patients who:
1. Have acromegaly due to reasons other than pituitary adenoma.
2. Have a pituitary adenoma that is less than 3mm distance from the optic chiasm.
3. Have undergone pituitary surgery within the 3 months preceding the Screening visit.
4. Have received pituitary radiotherapy within the 3 years preceding the Baseline visit.
5. Have insulin-treated diabetes.
6. Have congestive heart failure, unstable angina, clinically significant cardiac arrhythmia, or a history of acute myocardial infarction within the 3 months preceding the Baseline visit.
7. Have abnormal hepatic function at Screening defined as aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase, alkaline phosphatase, prothrombin time or total bilirubin above 2 x the upper limit of normal.
8. Have hepatitis B, hepatitis C, or chronic liver disease.
9. Are pregnant or lactating.
10. Have known human immunodeficiency virus (not tested specifically for this protocol), or history of immunodeficiency that may compromise their safety or affect results from this study.
11. Have a history of alcohol or drug abuse in the 6 month period preceding the Baseline visit.
12. Have participated in any clinical investigation with an investigational drug within 3 months (4 months if the drug is a new chemical entity) preceding the Baseline visit or during the washout period.
13. Have renal impairment with serum creatinine > or = 2.0 mg/dl (177 µmol/L).
14. Have a history of clinically relevant gastrointestinal, hepatic, renal, endocrine (other than acromegaly), haematological, metabolic, neurologic or psychiatric disease that in the investigator’s opinion may compromise their safety or effect results from this study.
15. Have a history of clinically significant coagulation abnormalities or complement fragment Bb abnormalities.
16. Have a history of severe or life-threatening drug allergy and/or known drug hypersensitivity.
17. Are unable to communicate or cooperate with the Investigator due to language problem, poor mental development or impaired cerebral function.
18. Have any other medical condition which, in the judgement of the Investigator, might interfere with the objectives of the study, or are otherwise unsuitable for participation.
19. Are unable to have a MRI performed due to metal residing in the body e.g. implants, cardiac pacemaker, valves, cochlear implants, central nervous system vascular clips etc.
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety and Tolerability Endpoints
- Incidence of Adverse Events
- Safety laboratory parameters, including haematology, biochemistry, coagulation, Complement Bb, GH, urinalysis
- Changes in vital signs
- Changes in 12-lead ECGs
- Pituitary tumour size changes
- Incidence and severity of injection site reactions
Pharmacokinetic Endpoints
- Determination of Cmax, Cmin, Tmax ,T1/2 and AUC of ATL1103
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety
- throughout treatment period (Day 1 to Week 14)
- during follow up period (Week 14 - Week 21)
Pharmacokinetics
- from pre and post dose serum samples at various dosing time points during 21 week study period |
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E.5.2 | Secondary end point(s) |
Primary Efficacy Endpoints
- Percentage change in IGF-I levels at Week 14 compared with Baseline
Secondary Efficacy Endpoints
- The proportion of patients whose IGF-I levels are normalised at Week 14.
- The proportion of patients whose IGF-I levels are normalised at any time point after baseline.
- The mean change in IGF-I from baseline to week 14.
- Change in GHBP, IGFBP-3, ALS, and IGF-II levels compared with Baseline.
- Change in Signs and Symptoms questionnaire compared with Baseline.
- Change in size of finger (as measured by the ring size assessment) at Week 14 compared to Baseline.
- Change in AcroQoL questionnaire at Week 14 compared to Baseline.
- Changes in GH, glucose and insulin from Screening OGTT to Week 14 OGTT. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Week 14 compared to Baseline |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Different treatment schedule of the same investigational product (ATL1103) |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 14 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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 | 1 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |