Phase IIa, Open Label, Dose Ascending Study to Determine the Maximum Tolerated Dose, Safety and Tolerability, Pharmacokinetics and Pharmacodynamics of a Single Dose of Lanreotide PRF in Subjects With Acromegaly Previously Treated and Controlled With Either Octreotide LAR or Lanreotide Autogel
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Ipsen
- 入组人数
- 28
- 试验地点
- 36
- 主要终点
- PK Analysis of Lanreotide: Maximum Observed Serum Concentration (Cmax).
研究概览
简要总结
The objectives of the protocol is to determine the maximum tolerated dose and to investigate the pharmacokinetics of a single dose of lanreotide PRF in subjects with acromegaly.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Documented diagnosis of acromegaly.
- •Provided written informed consent prior to any study related procedures.
- •Between 18 and 75 years of age inclusive.
- •Female of non-childbearing potential or male. Non-childbearing potential is defined as being postmenopausal for at least 1 year, or women with documented infertility (natural or acquired).
- •Male subjects must agree that, if their partner is at risk of becoming pregnant, they will use a medically accepted, effective method of contraception (i.e. condom) for the duration of the study (maximum of 7.5 months).
- •Treatment with a stable dose of either octreotide LAR or lanreotide Autogel for at least 3 months immediately prior to study entry, with confirmation of disease control during this treatment period (documentation of age adjusted IGF 1 <1.3 x upper limit of normal (ULN), based on local laboratory results, during screening period).
- •If the subject is receiving treatment for hypertension, the dose has been stable for at least 1 month prior to study entry.
- •Subjects must be willing and able to comply with study restrictions and to remain at the clinic for the required duration during the study period and willing to return to the clinic for the follow up evaluation as specified in the protocol.
排除标准
- •Has undergone radiotherapy within 2 years prior to study entry.
- •Has been treated with a dopamine agonist and/or GH receptor antagonist or has undergone pituitary surgery within 3 months prior to study entry.
- •Is anticipated to require pituitary surgery or radiotherapy during the study.
- •Has clinically significant hepatic abnormalities and/or alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≥3 x ULN and/or alkaline phosphatase (AP) ≥2.5 x ULN and/or total bilirubin ≥1.5 x ULN and/or gamma-glutamyl transpeptidase (GGT) ≥2.5 x ULN during the Screening period (central laboratory results) or a history of these findings when on somatostatin analogue (SSTa) treatment.
- •Has clinically significant pancreatic abnormalities and/or amylase and/or lipase ≥1.5 x ULN during the Screening period (central laboratory results).
- •Has any significant renal abnormalities and/or creatinine ≥1.5 x ULN during the screening period (central laboratory results).
- •Has uncontrolled diabetes (glycosylated haemoglobin (HbA1c) ≥9%, centrally assessed during the Screening period), or has diabetes treated with insulin for less than 6 months prior to study entry.
- •Has any known uncontrolled cardiovascular disease or had any of the following within 6 months of Screening: ventricular or atrial dysrhythmia
- •≥grade 2, bradycardia ≥grade 2, electrocardiogram (ECG) QT interval corrected (QTc) prolonged ≥grade 2, myocardial infarction, severe/unstable angina, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, pulmonary embolism, hypertension not adequately controlled by current medications.
- •Use of any hormone replacement therapy (HRT) with oestrogens.
- •Has symptomatic gallstones/ sludge at the Screening Visit echography (local assessment) OR is asymptomatic but has echography showing clear evidence of impending inflammation such as localised mucosal thickening suggesting the subject is at high risk of developing acute disease. Subjects with asymptomatic gallstones/ sludge and otherwise normal echography may be entered at the discretion of the investigator.
- •Has abnormal findings during the Screening period, any other medical condition(s) or laboratory findings that, in the opinion of the investigator, might jeopardise the subject's safety.
- •Has been treated with any other investigational medicinal product (IMP) prior to the first study visit without undergoing a washout period of seven times the elimination half-life of the investigational compound.
- •Has a known hypersensitivity to any of the test materials or related compounds.
- •Is likely to require treatment during the study with drugs that are not permitted by the study protocol.
- •Has a history of, or known current, problems with alcohol or drug abuse.
- •Has any mental condition rendering him/her unable to understand the nature, scope and possible consequences of the study, and/or evidence of an uncooperative attitude.
研究组 & 干预措施
lanreotide PRF
One single dose of lanreotide PRF (via subcutaneous injection) either 180mg or 270mg or 360mg.
干预措施: Lanreotide PRF (Drug)
结局指标
主要结局
PK Analysis of Lanreotide: Maximum Observed Serum Concentration (Cmax).
时间窗: From Baseline (pre-dose) up to Week 25.
Blood samples for determination of lanreotide serum concentrations were collected at Baseline (pre-dose), at 1, 2, 4, 6, 8,12 and 24 hours post-dose, on Days 3 and 5 and at Weeks 2, 3, 5, 9 and 13 after lanreotide PRF administration. Samples were also collected during follow-up at Weeks 17, 21 and 25 (or EW). Mean serum lanreotide Cmax values were determined using non-compartmental analysis.
Determination of the Maximum Tolerated Dose (MTD) by Number of Subjects With DLTs.
时间窗: From Day 1 up to Week 25.
The MTD was defined based on the DLTs observed in each cohort. A DLT was defined as an adverse event (AE) (excluding anorexia and fatigue) or an abnormal laboratory value occurring within the first week (up to Week 2) following lanreotide PRF administration and during the entire study duration, assessed as unrelated to acromegaly, intercurrent illness or concomitant medications and which met any of the pre-established toxicity criteria. If no DLTs were reported then no MTD could be defined.
PK Analysis of Lanreotide: Apparent Terminal Elimination Half-life (t1/2).
时间窗: From Baseline (pre-dose) up to Week 25.
Blood samples for determination of lanreotide serum concentrations were collected at Baseline (pre-dose), at 1, 2, 4, 6, 8,12 and 24 hours post-dose, on Days 3 and 5 and at Weeks 2, 3, 5, 9 and 13 after lanreotide PRF administration. Samples were also collected during follow-up at Weeks 17, 21 and 25 (or EW). Mean serum lanreotide t1/2 values were determined using non-compartmental analysis. Only values fulfilling the determination rules for t1/2 were analysed.
PK Analysis of Lanreotide: Time to Reach Maximum Serum Concentration (Tmax).
时间窗: From Baseline (pre-dose) up to Week 25.
Blood samples for determination of lanreotide serum concentrations were collected at Baseline (pre-dose), at 1, 2, 4, 6, 8,12 and 24 hours post-dose, on Days 3 and 5 and at Weeks 2, 3, 5, 9 and 13 after lanreotide PRF administration. Samples were also collected during follow-up at Weeks 17, 21 and 25 (or EW). Median serum lanreotide Tmax values were determined using non-compartmental analysis.
PK Analysis of Lanreotide: Area Under the Serum Concentration-time Curve From Time 0 to 85 Days (AUC0-85).
时间窗: From Baseline (pre-dose) up to Day 85
Blood samples for determination of lanreotide serum concentrations were collected at Baseline (pre-dose), at 1, 2, 4, 6, 8,12 and 24 hours post-dose, on Days 3 and 5 and at Weeks 2, 3, 5, 9 and 13 after lanreotide PRF administration. Sample were also collected during follow-up at Weeks 17, 21 and 25 (or EW). Mean serum lanreotide AUC0-85 values were determined using non-compartmental analysis.
PK Analysis of Lanreotide: Area Under the Serum Concentration-time Curve Extrapolated to Infinity (AUC0-∞).
时间窗: From Baseline (pre-dose) up to Week 25.
Blood samples for determination of lanreotide serum concentrations were collected at Baseline (pre-dose), at 1, 2, 4, 6, 8,12 and 24 hours post-dose, on Days 3 and 5 and at Weeks 2, 3, 5, 9 and 13 after lanreotide PRF administration. Samples were also collected during follow-up at Weeks 17, 21 and 25 (or EW). Mean serum lanreotide AUC0-∞ values were determined using non-compartmental analysis. Only values fulfilling the accuracy determination rules for AUC0-∞ were analysed.
次要结局
- PK Analysis of Glycofurol Excipients: AUC0-∞ and Area Under the Serum Concentration Time Curve From Time 0 to Last Quantifiable Timepoint (AUC0-t).(From Baseline (pre-dose) up to Day 5.)
- PD Analysis: Mean Change From Baseline in Free Triiodothyroxine (FT3) and Free Thyroxine (FT4).(From Baseline (pre-dose) up to Week 25.)
- Overall Summary of Number of Subjects With AEs.(From Day -42 up to Week 25.)
- PK Analysis of Glycofurol Excipients: Cmax.(From Baseline (pre-dose) up to Day 5.)
- PK Analysis of Glycofurol Excipients: Tmax.(From Baseline (pre-dose) up to Day 5.)
- PD Analysis: Mean Change From Baseline in Insulin-like Growth Factor 1 (IGF-1).(From Baseline (pre-dose) up to Week 25.)
- PD Analysis: Mean Change From Baseline in Thyroid Stimulating Hormone (TSH).(From Baseline (pre-dose) up to Week 25.)
- PD Analysis: Mean Change From Baseline in Growth Hormone (GH).(From Baseline (pre-dose) up to Week 13.)
- PD Analysis: Mean Change From Baseline in Prolactin.(From Baseline (pre-dose) up to Week 25.)