Change in Quality of Life After Addition of Weekly 40 mg Pegvisomant/Placebo in Controlled Acromegalic Patients
Condition: Quality of Life; Acromegaly
MeSH terms: Acromegaly
Study type: Interventional
Phase: Phase 4

Summary: 
      Study Synopsis Study Title: Double blind, single centre, cross-over study on the effects of
      weekly subcutaneous administration of 40 mg pegvisomant or placebo on quality of life and
      insulin sensitivity in acromegalic patients with normal serum IGF-I concentrations during
      long-term treatment with long-acting somatostatin analogs

      Study Objectives:

        1. To determine whether the addition of weekly pegvisomant administrations improves quality
           of life

        2. To determine whether the addition of weekly pegvisomant administrations improves insulin
           sensitivity

      Study Population: Acromegalic patients, who have normalized their serum IGF-I levels down to
      the upper 25 centiles of normality during long-term treatment with monthly injections of a
      long-acting somatostatin analogue Number of Subjects: 20

      Procedures:

        -  Patients on treatment with Sandostatin LAR (SL) 20 - 30 mg per months i.m. or patients
           on treatment with Lanreotide autosolution (LA) 90 - 120 mg deep s.c. will be enrolled.

        -  For 4 months, all subjects will also receive weekly s.c. injections of either placebo or
           a fixed dose of 40 mg pegvisomant

        -  After a 4 weeks wash-out period, patients will switch from either placebo to pegvisomant
           or from pegvisomant to placebo

        -  Before, and after 2 and 4 months of each treatment period, serum efficacy parameters and
           quality of life (AcroQol ™/ PASQ™) will be assessed.

        -  Before and after 4 months of each treatment period, pituitary tumor size and insulin
           sensitivity (HOMA/SIGMA model) will be assessed. Duration of study: 9 months

      Hypothesis:

      •We postulate that co-administration of the growth hormone receptor antagonist pegvisomant
      will improve QoL and insulin sensitivity
    

Detailed description: 
      Introduction Both lanreotide (Somatulin Autosolution ™ (SL)) and octreotide (Sandostatin LAR
      ™ (LAR)) are equally effective in controlling disease activity in acromegalic subjects with a
      normalization of serum insulin-like growth factor-I (IGF-I) levels in roughly 65%. However,
      SL is injected as a deep intramuscular injection, while LA is injected as a deep subcutaneous
      injection. Physicians, involved in the treatment of acromegalic patients know that
      biochemical control of the disease in their patients not necessarily means that all those
      patients stop complaining. To address these issues, Sonino and co-workers studied with
      several symptom questionnaires the effects on quality of life (QoL) of SL. Together with a
      significant decrease in growth hormone (GH) and IGF-I, treatment with SL significantly
      improved psychological distress, well-being and social fears (1). In another study on the
      efficacy of the novel GH receptor antagonist pegvisomant to lower serum IGF-I concentrations
      a questionnaire evaluating five clinical signs and symptoms of acromegaly showed dose
      dependent significant differences from placebo (2). Recently, Webb and co-workers reported
      the successful development of a disease-specific questionnaire suitable to measure
      health-related quality of life in acromegaly (ACROQOL) (3).

      No clear biochemical parameter appears to be available that correlates well with disease
      activity related quality of life (4). At the same time, serum GH concentrations and serum
      total IGF-I levels, but not QoL, are used as parameters to determine dosing of Sandostatin
      LAR, or any of the available medical therapies for acromegaly (5-8).

      The growth hormone receptor antagonist pegvisomant as monotherapy once daily normalizes IGF-I
      in virtually all acromegalics (9;10), but pegvisomant monotherapy is also very costly.
      Recently, we reported the results of a 42-week dose-finding study on the efficacy of the
      combination of long-acting somatostatin analogues once monthly and pegvisomant once weekly in
      26 patients with active acromegaly. Pegvisomant dose was increased until IGF-I levels
      normalized or until a weekly dose of 80 mg was reached. IGF-I levels normalized in 25 (95 %)
      with a median weekly dose of 60 mg pegvisomant. There were no signs of pituitary tumor growth
      but mild elevations in liver enzymes were observed in 10 patients (38%) (11). One of the
      potential advantages of combining pegvisomant with somatostatin analogues is that pegvisomant
      monotherapy improves insulin sensitivity compared to somatostatin analogues (12;13), although
      it is unclear yet whether or not long-term pegvisomant administration would improve insulin
      sensitivity in normal subjects (13;14). Therefore, one might expect that pegvisomant
      monotherapy has beneficial effects on insulin sensitivity, compared to the combination of
      both pegvisomant and somatostatin analogues, as the latter ones decrease insulin sensitivity
      by several mechanisms (13;15).

      Conclusion:

        -  So-called biochemically well controlled acromegalic subjects with normal serum IGF-I
           concentrations frequently still have an impaired QoL.

        -  These subjects, when controlled by long-acting somatostatin analogs have impaired
           insulin sensitivity because of the pharmacological properties of these somatostatin
           analogs.

        -  We postulate that co-administration of the growth hormone receptor antagonist
           pegvisomant will improve QoL and insulin sensitivity

      Objectives:

        1. To determine whether the addition of weekly pegvisomant administrations improves quality
           of life

        2. To determine whether the addition of weekly pegvisomant administrations improves insulin
           sensitivity

      Description of procedures:

        -  Patients on treatment with Sandostatin LAR (SL) 20 - 30 mg per months i.m. or patients
           treated with Lanreotide autosolution (LA) 90 - 120 mg deep s.c. will be enrolled.

        -  For 4 months, and after randomization, all subjects will also receive weekly s.c.
           injections of either placebo or a fixed dose of 40 mg pegvisomant

        -  After a 4 weeks wash-out period, patients will switch from either placebo to pegvisomant
           or from pegvisomant to placebo

        -  Before, and after 2 and 4 months of each treatment period, serum efficacy parameters and
           quality of life (AcroQol ™ , general QoL questionaire and PASQ Signs and Symptoms) will
           be assessed.

        -  Before and after 4 months of each treatment period, pituitary tumor size and insulin
           sensitivity (HOMA/SIGMA model (16)) will be assessed.

      Subjects Twenty acromegalic subjects who are seen at regular intervals at our out-patient
      facilities will be asked to participate. All subjects will be seen at the Clinical Research
      Unit.

      Inclusion criteria:

        -  Active acromegaly.

        -  Serum total IGF-I levels must have been normalized during long-term treatment with
           long-acting somatostatin analogs

        -  Age between 18 and 80

      Exclusion criteria:

        -  Any contra-indication for the use of long-acting somatostatin analogs, as e.g. the use
           of anti-coagulants.

        -  Subjects with pituitary tumors that compress the optic chiasm

        -  Patients with insulin dependent diabetes

        -  Patients with cancer

        -  Patients with kidney- or liver function disturbances

        -  Fertile female patients that refuse to take contraceptives during the study

      Study procedures Visit 1; baseline (week 0; 1 day prior to next monthly injection of
      long-acting SRIF analog))

        -  Review inclusion and exclusion criteria

        -  Obtain written informed consent

        -  Conduct a medical history and physical examination; record vital signs.

        -  Blood sampling: fasting IGF-I, insulin, GH, glucose, HbA1c, liver functions, lipid
           profile, free fatty acids, pegvisomant levels, pregnancy test in females.

        -  QoL assessment (AcroQol™/PASQ ™)

        -  MRI (recent MRI of < 3 months is also acceptable)

        -  Injection of the usual SL or LA dose

        -  randomization

        -  Start of weekly injections of 40 mg pegvisomant or placebo (16 injections in total)

      Visit 2, 3 (week 8 and 16; one day prior of weekly study drug/placebo injection)

        -  Blood sampling: fasting IGF-I, insulin, GH, glucose, HbA1c, liver functions, lipid
           profile, free fatty acids, pegvisomant levels

        -  QoL assessment (AcroQol™/PASQ ™)

        -  After week 16, all patients have their 4 weeks wash-out period

        -  MRI

      Visit 4 (week 20; end of wash-out)

        -  Blood sampling: fasting IGF-I, insulin, GH, glucose, HbA1c, liver functions, lipid
           profile, free fatty acids, pegvisomant levels

        -  Return of study medication for drug accountability

        -  QoL assessment (AcroQol™/PASQ ™)

        -  Start of second co-treatment period with weekly s.c injections of either placebo or 40
           mg fixed-dose pegvisomant (16 weekly injections)

      Visit 5, 6 (week 28 and 36; one day prior of weekly study drug/placebo injection)

        -  Blood sampling: fasting IGF-I, insulin, GH, glucose, HbA1c, liver functions, lipid
           profile, free fatty acids, pegvisomant levels

        -  Return of study medication for drug accountability

        -  QoL assessment (AcroQol™/PASQ ™)

        -  MRI
    

Intervention name(s): Pegvisomant
Intervention type(s): Drug
Intervention description(s): if the addition of 40 mg pegvisomant weekly will improve the quality of life of acromegaly patients compared to placebo weekly
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment