Pasireotide LAR and Pegvisomant Study in Acromegaly (PAPE)

• ClinicalTrials.gov Identifier: NCT02668172
• Recruitment Status: Unknown
• First Posted: January 29, 2016
• Last Update Posted: August 3, 2016
• Sponsor: Erasmus Medical Center
• Collaborator: Novartis
• Information provided by (Responsible Party): s neggers, Erasmus Medical Center

Study Description

Brief Summary:

The objective of this study is to assess the efficacy of Pasireotide Long Acting Release (LAR) alone and in combination with weekly Pegvisomant (PEGV) in acromegaIy patients previously controlled with combination treatment of long-acting Somatostatin analogs (LA-SSAs) and PEGV.

Condition or disease	Intervention/treatment	Phase
Acromegaly	Drug: Pasireotide LAR 60 mg; Drug: Pegvisomant	Phase 4

Detailed Description:

Pasireotide Long Acting Release (Signifor ®), a novel long-acting multi-receptor ligand somatostatin analogue, has been shown to be more effective for the treatment of GH-secreting pituitary adenomas than currently used long-acting somatostatin analogues (LA-SSAs). The long-term efficacy of acromegaly patients using LA-SSAs in combination with PEGV was over 90% in terms of normalization of IGF-I. The combination of PEGV with pasireotide LAR has not been studied yet. Combining PEGV with pasireotide LAR could result in a lower dose and less injections of pegvisomant. This may ultimately lead to a more cost-effective treatment and improved quality of life.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 60 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Efficacy and Safety of Pasireotide Long Acting Release (LAR) in Combination With Weekly Pegvisomant in Previously Controlled Acromegaly Patients on Combination Treatment of Long-Acting Somatostatin Analogues and Weekly Pegvisomant
• Study Start Date: August 2015
• Estimated Primary Completion Date: March 2017
• Estimated Study Completion Date: June 2017

Arms and Interventions

Arm	Intervention/treatment
Experimental: Pasireotide LAR 60 mg monotherapy week 12; After enrollment, acromegaly patients on combination treatment will half their regular weekly dose of pegvisomant (PEGV) for 12 weeks (run-in period). When insuline-like growth factor 1 (IGF‐I) remains within the age adjusted normal limits after 12 weeks, PEGV and the LA-SSA (Octreotide Long Acting Release (LAR) or Lanreotide Autogel) with Pegvisomant (PEGV) are discontinued and patients are switched to pasireotide LAR 60 mg for 12 weeks.	Drug: Pasireotide LAR 60 mg; as mono-therapy or in combination with pegvisomant; Other Name: Signifor, SOM230
Experimental: Pasireotide LAR 60 mg and Pegvisomant week 12; When IGF-I rises above the adjusted normal limits after 12 weeks (run-in period), these subjects will switch their LA-SSA to Pasireotide LAR 60 mg every 4 weeks and continue with the reduced PEGV dose of the run-in period, for the remaining 12 weeks.	Drug: Pasireotide LAR 60 mg; as mono-therapy or in combination with pegvisomant; Other Name: Signifor, SOM230; Drug: Pegvisomant; only in combination with pasireotide LAR; Other Name: Somavert
Experimental: Pasireotide LAR 60 mg and Pegvisomant week 24; Between week 12 and 24 dose adaptations of PEGV are not permitted unless IGF-I drops below the age adjusted normal limits, then the dose of PEGV will be decreased stepwise with 20 mg weekly until IGF-I is within the age adjusted normal limits. At week 24, efficacy will be assessed, as the number of patients with a normal IGF-I in the two different groups; the combination Pasireotide LAR 60 mg / PEG V dose and monotherapy Pasireotide LAR 60 mg. From week 24 patients will continue with Pasireotide LAR 60 mg monotherapy, or Pasireotide LAR will be combined with 50% of the original dose of PEGV, or with an increasing dose of PEGV every 8 weeks depending on the treatment arm.	Drug: Pasireotide LAR 60 mg; as mono-therapy or in combination with pegvisomant; Other Name: Signifor, SOM230; Drug: Pegvisomant; only in combination with pasireotide LAR; Other Name: Somavert

Outcome Measures

Primary Outcome Measures :

1. The proportion of patients with normalized IGF1 levels at 24 weeks in the pasireotide LAR monotherapy group and in the pasireotide LAR combined with pegvisomant group [ Time Frame: 24 weeks ]

Secondary Outcome Measures :

1. The proportion of patients with normalized IGF1 levels after 48 weeks of pasireotide LAR monotherapy [ Time Frame: 48 weeks ]
2. The proportion of patients with normalized IGF1 levels after 48 weeks combination treatment of pasireotide LAR with weekly pegvisomant. [ Time Frame: 48 weeks ]
3. The necessary dose of pegvisomant during combination treatment of pasireotide LAR with pegvisomant in patients with an IGF-I level within the age adjusted normal limits [ Time Frame: 48 weeks ]
4. Change in tumor volume by pituitary MRI [ Time Frame: Baseline and 48 weeks ]
5. Tolerability and safety profile of pasireotide Long Acting Release (LAR) monotherapy [ Time Frame: 48 weeks ]
   Toxicity will be assessed using the National Cancer Institute-Common Toxicology Criteria Adverse Events version 4 (NCI-CTCAE v.4.03) and for laboratory assessments that include biochemistry, hematology, urinalysis; special safety assessments that include the regular monitoring and recording of blood glucose, insulin, HbA1c, GH and IGF-1, thyroid and liver function tests, gallbladder examinations and ECGs. Concomitant medications/Significant nondrug therapies will be assessed from study enrollment until the safety follow-up.
6. Tolerability and safety profile of pasireotide LAR and pegvisomant combination therapy [ Time Frame: 48 weeks ]
   Toxicity will be assessed using the National Cancer Institute-Common Toxicology Criteria Adverse Events version 4 (NCI-CTCAE v.4.03) and for laboratory assessments that include biochemistry, hematology, urinalysis; special safety assessments that include the regular monitoring and recording of blood glucose, insulin, HbA1c, and IGF-1, thyroid and liver function tests, gallbladder examinations and ECGs. Concomitant medications/Significant nondrug therapies will be assessed from study enrollment until the safety follow-up.
7. Evaluation of long term effect of pasireotide LAR with or without pegvisomant on AcroQol, PASQ and signs and symptoms of acromegaly [ Time Frame: Change in scores as measured by AcroQoL from baseline to week 48 ]
   AcroQol is quality of life questionnaire specifically designed for acromegaly
8. Evaluation of long term effect of pasireotide LAR with or without pegvisomant on AcroQol, PASQ and signs and symptoms of acromegaly [ Time Frame: Change in scores as measured by PASQ from baseline to week 48 ]
   PASQ are questionnaire for the disease specific symptoms
9. Evaluation of long term effect of pasireotide LAR with or without pegvisomant on AcroQol, PASQ and signs and symptoms of acromegaly [ Time Frame: Description of signs and symptoms of acromegaly ]
10. Evaluation of body composition by Dual-energy X-ray Absorptiometry (DEXA) scan [ Time Frame: baseline and 48 weeks ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• written informed consent male or female aged ≥ 18 years
• documentation supporting the diagnosis of acromegaly based on elevated GH and/or IGF-I levels due to a pituitary tumor
• the patient is treated with lanreotide Autogel or octreotide LAR and PEGV (twice) weekly for at least 6 months and has a serum IGF-I level within 120 % of the age adjusted normal limits. These patients were previously not controlled by somatostatin analogs alone.
• female of no childbearing potential or male. No childbearing potential is defined as being postmenopausal for at least 1 year, or women with documented infertility (natural or acquired) or using two acceptable contraceptive measures, except for oral contraceptives.
• 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. use a condom) for the duration of the study
• 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.

Exclusion Criteria:

Patients will not be included in the study if he or she:

• has undergone pituitary surgery or radiotherapy within 6 months prior to study entry.
• it is anticipated that the patient will receive pituitary surgery or radiotherapy during the study.
• has a history of hypersensitivity to lanreotide, octreotide or pegvisomant or drugs with a similar chemical structure
• has been treated with any unlicensed drug within the last 30 days before study entry.
• has abnormal hepatic function at study entry (defined as AST, ALT, gGT, alkaline phosphatase, or total bilirubin above 3 ULN)
• is at risk of pregnancy or is lactating. Females of childbearing potential must provide a negative pregnancy test within 5 days before the start of the study and must be using contraception. Non-childbearing potential is defined as post-menopause for at least one year, surgical sterilization or hysterectomy at least three months before the start of the study.
• has a history of, or known current problems with alcohol or drug abuse.
• has a mental condition rendering the subject unable to understand the nature, scope and possible consequences of the study, and/or evidence of an uncooperative attitude.
• has abnormal baseline findings, any other medical condition(s) or laboratory findings that, in the opinion of the investigator, might jeopardize the subject's safety or decrease the chance of obtaining satisfactory data needed to achieve the objective(s) of the study.
• renal insufficiency, clearance < 50ml/min
• poorly controlled diabetes mellitus with an HbA1c > 9.0%
• patients with a QTc > 500 ms on the EKG
• participation in a clinical trial in the last 6 months

Contacts and Locations

Locations

Netherlands

Erasmus Medical Center

Rotterdam, South Holland, Netherlands, 3000CA

Sponsors and Collaborators

Erasmus Medical Center

Novartis

Investigators

• Principal Investigator: Sebastian Neggers, MD PhD; Erasmus MC

More Information

Additional Information:

Summary of study at Dutch Trial Register  Summary of study at the WHO International Clinical Trials Registry Platform 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Muhammad A, van der Lely AJ, Delhanty PJD, Dallenga AHG, Haitsma IK, Janssen JAMJL, Neggers SJCMM. Efficacy and Safety of Switching to Pasireotide in Patients With Acromegaly Controlled With Pegvisomant and First-Generation Somatostatin Analogues (PAPE Study). J Clin Endocrinol Metab. 2018 Feb 1;103(2):586-595. doi: 10.1210/jc.2017-02017.

• Responsible Party: s neggers, Consultant endocrinology, Erasmus Medical Center
• ClinicalTrials.gov Identifier: NCT02668172 History of Changes
• Other Study ID Numbers: NL49517.078.14; 2014-002219-41 ( EudraCT Number ); NTR5282 ( Registry Identifier: Dutch Trial Register )
• First Posted: January 29, 2016
• Last Update Posted: August 3, 2016
• Last Verified: August 2016

Keywords provided by s neggers, Erasmus Medical Center:

pegvisomant; pasireotide LAR; long acting somatostatin analogues

Additional relevant MeSH terms:

Acromegaly; Bone Diseases, Endocrine; Bone Diseases; Musculoskeletal Diseases; Hyperpituitarism; Pituitary Diseases; Hypothalamic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Endocrine System Diseases; Somatostatin; Pasireotide; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs