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Cochrane Database of Systematic Reviews Protocol - Intervention

Somatostatin analogues, dopamine agonists or growth hormone antagonists for pituitary adenoma‐induced acromegaly.

Authors' declarations of interest

Version published: 20 January 2010 Version history

https://doi.org/10.1002/14651858.CD008292

This is not the most recent version

view the current version 16 November 2015
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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the effects of somatostatin analogues, dopamine agonists or growth hormone antagonists for pituitary adenoma‐induced acromegaly.

Background

Acromegaly is a rare endocrine disorder characterized by an increased growth hormone (GH) secretion mostly from a pituitary adenoma (AACE Guideline 2004; Kauppinen‐Makelin 2005). The condition is due to an excess growth hormone secression occurring after closure of growth plates. The estimated annual incidence of the disease is about 3 to 4 cases per one million inhabitants (Colao 2004). It is associated with significant morbidity and mortality related to underlining conditions such as diabetes, respiratory, cardiovascular and cerebrovascular diseases in those affected. The presence of acromegaly increases mortality by 2 to 3 folds and the disease is associated with a reduction in life expectancy of about 10 years compared to the general population (Ayuk 2008; Biermasz 2005).

Description of the condition

The clinical feature commonly results from an increase in GH levels due to a growth hormone secreting pituitary tumour or from the production of growth hormone releasing hormone (GHRH) by other tumours (lungs, pancreas and adrenal glands). This review concerns acromegaly due to an increased growth hormone secression due to a pituitary adenoma. The condition includes myocardial dysfunction, hyperhidrosis, soft‐tissue swelling, headaches, coarsening of facial features and enlargement of the hands and feet (AACE Guideline 2004; Ben‐Shlomo 2006). Clinical signs are very important for the diagnosis of acromegaly (Ben‐Shlomo 2008a). The diagnosis is confirmed in the presence of elevated levels of insulin‐like growth factor 1 (IGF‐1) and the failure of normal GH suppression in response to an oral glucose load (Biering 2006; Freda 2006; Melmed 1998).

Description of the intervention

The goals of the treatment are to control the signs and symptoms of the disease and to achieve near normal levels of biochemical markers (Melmed 1998; Melmed 2002).

Among the available treatment approaches to achieve these goals, surgery is considered as the first line treatment (Merza 2003). Radiotherapy and pharmacological treatment are used as adjuvant approaches. To this end, treatment with somatostatin analogous is considered as the most effective adjuvant therapy. Some studies have shown that target hormonal ranges are achieved in only 50% to 60% of patients following surgical intervention (Lamberts 1998; Melmed 2002). In those remaining, adjuvant pharmacological treatment is needed to reach the targets (Table 1).

Open in table viewer
Table 1. Drugs used for treatment of acromegaly

drug type and agent

starting dose

maximal dose

typical side effects

monitoring suggestions

preferred indication

Dopamine agonist

Cabergoline

1 mg/wk

per os

4 mg per week

nausea, GI cramps, gallstones

GH, IGF‐1

GH and prolactin co‐secreting tumours

Somatostatin analogous

Octreotide

50 mg sc t.i.d

200 mg t.i.d.

nausea, GI cramps, gallstones

GH, IGF‐I, ultrasonography of gallbladder (if symptomatic)

somatostatin analogous responsive tumours

Octreotide LAR

10 mg  i.m.
every 4 weeks

30 mg i.m.
every 4 weeks

nausea, GI cramps, gallstones 

GH, IGF‐I, ultrasonography of gallbladder (if symptomatic)

somatostatin analogous responsive tumours

Octreotide

60 mg i.m.
every 2 weeks

120 mg i.m.
every 7 days

nausea, GI cramps, gallstones 

GH, IGF‐I, ultrasonography of gallbladder (if symptomatic)

somatostatin analogous responsive tumours

Lanreotide autogel

60 mg i.m.
every 4 weeks

120 mg i.m.
every 4 weeks

nausea, GI cramps, gallstones 

GH, IGF‐I, ultrasonography of gallbladder (if symptomatic)

somatostatin analogous responsive tumours

GH antagonist

Pegvisomant

10 mg s.c. daily

40 mg daily 

headache, fatigue, abnormal liver enzymes

liver function test for 6 months then every 6 months,

MRI yearly, IGF‐1 only (not GH)

high IGF‐1 not responsive to somatostatin analogous therapy

GH: growth hormone; GI: gastrointestinal; IGF‐I: insulin‐like growth factor‐I; i.m.: intramuscular; LAR: long‐acting release; MRI: magnetic resonance imaging; s.c.: subcutaneous; t.i.d: three times a day

Elsewhere, pharmacological treatment, in particular the use of somatostatin analogous has been suggested as first line approach to acromegaly (Ayuk 2004; Bollerslev 2009; Chanson 2008). Other pharmacological agents available for use in the treatment of acromegaly include dopamine agonists and GH receptor antagonists (Lamberts 1998).

Adverse effects of the intervention

The side effects associated with somatostatin use include symptomatic cholesterol gallstones which occur in about 25% of cases, abdominal discomfort (abdominal pain, nausea, diarrhoea, flatulence) and bradycardia (Ezzat 1992).

Typical side effects of dopamine agonists include nausea, vomiting, abdominal cramps and postural hypotension.

Growth hormone receptor antagonists correlate with increased transaminase levels.

How the intervention might work

Somatostatin analogous

These molecules are derivatives of growth hormone and follow the same physiological pathway as the naturally occurring somatostatin hormone. The two most active isoforms have 14 and 28 amino acids respectively. GH secreting tumours express five different subtypes of somatostatin receptors (SSTR1‐5) (Bronstein 2006).The SSTR2 receptor subtype is an important mediator for the suppression of GH secretion (Ben‐Shlomo 2008b). GH analogous have been classified into two generations according to their half‐life and duration of action. Analogs of the first generation (octreotide) have a half‐life of two hours and achieve a maximum hormonal suppressive effect within similar duration. Treatment with octreotide requires at least three subcutaneous injections per day to account for the short total duration of action of six hours. This treatment reduces GH and IGF‐1 in 50% to 70% of patients. It also normalizes the IGF‐1 in about 64% of patients. Modest tumour shrinkage can occur with octreotide; it is therefore a suboptimal treatment (Melmed 2006). In some patients, the number of injections needs to be increased because of GH rapid returns to baseline levels as a consequence of the short duration of the pharmacological effect of the drug. To address this shortcoming, long‐acting somatostatin analogous have been developed. These include the long‐acting release (LAR) form of octreotide which is injected intramuscularly every 28 days. The second long‐acting somatostatin analogue is lanreotide which is available as lanreotide LAR for intramuscular injections every 10 to 14 days and lanreotide autogel for subcutaneous injections every 28 days. The patient’s response to short acting somatostatin analogous should be assessed before prescription of long‐acting analogous.

Dopamine agonists

Dopamine increases GH levels in healthy individuals. On the other hand it decreases GH secretion in patients treated for acromegaly. About 30% of pituitary adenomas secrete GH and prolactin. Dopamine antagonists usually achieve good results for this type of tumour (Annamaria 1997). Dopamine agonists include bromocriptine, cabergoline, pergolide, lisuride and quinagolide. The most frequently used dopamine agonists are bromocriptine and cabergoline.

Bromocriptine is the only dopamine agonist licensed for the treatment of acromegaly. It was used in this indication for the first time by Chiodini and his colleagues in 1974 (Chiodini 1974). Bromocriptine is a short acting analogue which is given two to four times a day per os. Despite limited effects on biomarkers levels, patients experience some clinical improvement. This improvement is likely achieved with drug doses in the range of 15 to 20 mg daily, with increased risk of side effects (like nausea, vomiting, abdominal cramps, postural hypotension) (Melmed 1998).

Cabergoline is a newly developed dopamine agonist. It is more potent than bromocriptine with fewer side effects (Abs 1998).

GH receptor antagonists

GH receptor antagonists are newly developed therapeutic weapons for acromegaly. The only marketed member of this group is pegvisomant. Pegvisomant is a genetically developed GH antagonist. It prevents the demineralization and signalling of the GH receptors. In so doing, it reduces the production of IGF‐1 (Hodish 2008). Unlike other drugs used for the treatment of acromegaly, pegvisomant only reduces the IGF‐1 without affecting GH level. This action is obtained through a proportional dose‐response effect. It is the most effective medical therapy to normalize IGF‐1 levels. The treatment is administered subcutaneously. The side effects include elevation of transaminase levels which can lead to treatment discontinuation (Biering 2006; Hodish 2008). In the follow up of patients, liver function tests should therefore be performed monthly for the first six months (Melmed 2006). Some studies suggest that long‐term treatment with GH receptor antagonists improves acromegaly associated cardiomegaly by improving systolic and diastolic function as well as reducing the ventricular hypertrophy (Pivonello 2007).

Why it is important to do this review

Though the prevalence of acromegaly is low, the mortality and morbidity associated with the disease are high. It is therefore important to have a standardized treatment protocol for management of the condition. Many studies have been carried out, however the place of the medical treatment for acromegaly still remains unclear. As a result, this review aims to identify and summarise available evidence pertaining to specific pharmacological treatment of acromegaly.

Objectives

To assess the effects of somatostatin analogues, dopamine agonists or growth hormone antagonists for pituitary adenoma‐induced acromegaly.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials. We will include trials with follow up of at least three months.

Types of participants

Adult patients with acromegaly. Patients will be distinguished according to primary or secondary medical treatment (prior or after surgery) and the treatment given with possible combinations.

Diagnostic criteria

  • lack of suppression or paradoxical rise in growth hormone (GH) levels after an oral glucose tolerance (oGTT) test in a patient with suggestive clinical signs and elevated basal insulin‐like growth factor 1 (IGF‐1) levels (compared to age and sex specific reference ranges);

  • pituitary tumour confirmed by magnetic resonance imaging (MRI).

Types of interventions

Intervention

  • somatostatin analogues;

  • dopamine agonists;

  • growth hormone receptor antagonists;

  • combination of somatostatin analogous and dopamine agonists.

Control

  • placebo;

  • no therapy;

  • surgery;

  • radiotherapy.

Types of outcome measures

Primary outcomes

  • hormonal profile (this includes baseline and follow up GH and IGF‐I levels. GH suppression test results will be considered and the results will be examined according to the normal range except for patients treated with GH receptors antagonists. IGF‐I results will be examined according to the reference ranges. The average change in GH and IGF‐I levels will be considered as indicator of the response to treatment. Both GH and IGF‐1 levels will not be used for dopamine agonists because of their minor effects on these biomarkers);

  • death from any cause;

  • cure rate (this is the proportion of patients in whom control is achieved following initiation of any of the drug treatments for acromegaly. Control will be considered achieved when all attributes of disordered GH secretion are restored to normal. This will be evidenced by the reduction of circulating IGF‐I to the normal age‐specific range, and a nadir GH below 1 ng/mL after an oral glucose tolerance test (Andrea 2000)).

Secondary outcomes

  • tumour shrinkage (this corresponds to a reduction of the tumour’s size after treatment initiation);

  • morbidity (morbidity will be especially examined as new onset, persistence or good control (treatment) of diabetes mellitus, high blood pressure and cardiac dysfunction (such as left ventricular hypertrophy and abnormality of left ventricular diastolic function));

  • adverse effects (these are specific side effects of the different classes of drugs used for the treatment of acromegaly);

  • health‐related quality of life;

  • costs.

Covariates, effect modifiers and confounders

  • age;

  • compliance to the treatment;

  • duration of treatment;

  • past medical history of diabetes, high blood pressure or cardiovascular disease.

Timing of outcome measurement

  • short term: three to six months after the beginning of treatment;

  • medium term: six to twelve months after the beginning of treatment;

  • long term: more than one year after the beginning of treatment.

Search methods for identification of studies

Electronic searches

We will use electronic searches to identify relevant trials, reviews and meta‐analyses. We will search the following databases:

  • The Cochrane Library (latest issue);

  • MEDLINE (until recent);

  • EMBASE (until recent).

Ongoing trials will be searched in the following databases:

For detailed search strategies please see under Appendix 1.

Additional key words of relevance may be detected during any of the electronic or other searches. If this is the case, electronic search strategies will be modified to incorporate these terms. Studies published in any language will be included.

Searching other resources

Authors of relevant trials or reviews will be contacted to obtain more information about their studies, ongoing trials or unpublished trials.

We will try to identify and to obtain additional studies by searching reference list of relevant trials and (systematic) reviews, meta‐analyses and health technology assessment reports noticed.

Data collection and analysis

Selection of studies

Trials to be included will be selected by two authors independently (AEA, EBV) using a standard data extraction form (see 'Characteristics of included studies', Table 2 and Appendix 2). Any disagreement will be resolved by consensus. Two other authors (ES, APK) will independently identify the studies to further assess. They will scan the titles, abstracts and the key words of articles retrieved. They will ensure that the selected trials fulfil the inclusion criteria: 1. include patients with acromegaly, 2. study at least one of the pharmacological treatments for acromegaly, 3. study the outcome of at least one of the pharmacological treatments for acromegaly, and 4. use random allocation of patients.

Open in table viewer
Table 2. Overview of study populations

study ID

intervention (I)
control (C)

[n] screened

[n] randomised

[n] safety

[n] ITT

[n] finishing study

[%] of randomised
participants
finishing study

comments

ID1

I1: Intervention 1
I2: Intervention 2
C1: Control 1
C2: Control 2

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

ID2

I1: Intervention 1
I2: Intervention 2
C1: Control 1
C2: Control 2

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

ID3

I1: Intervention 1
I2: Intervention 2
C1: Control 1
C2: Control 2

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

ID4

I1: Intervention 1
I2: Intervention 2
C1: Control 1
C2: Control 2

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

ID5

I1: Intervention 1
I2: Intervention 2
C1: Control 1
C2: Control 2

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

ID6

I1: Intervention 1
I2: Intervention 2
C1: Control 1
C2: Control 2

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

ID7

I1: Intervention 1
I2: Intervention 2
C1: Control 1
C2: Control 2

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

ID8

I1: Intervention 1
I2: Intervention 2
C1: Control 1
C2: Control 2

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

ID9

I1: Intervention 1
I2: Intervention 2
C1: Control 1
C2: Control 2

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

Total

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

ITT: intention‐to‐treat

In case of any doubt regarding one of these criteria, the full article will be retrieved for more details. The level of agreement between independent authors will be assessed with the use of the kappa statistic (Cohen 1960). Where differences of opinion exist, they will be resolved by consensus. If necessary, authors will be contacted for more information; then, the article will be recorded with 'awaiting assessment' until discrepancies are resolved. If not resolved, the opinion of the Editorial Base will be requested.

We will attach an adapted PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) flow‐chart of study selection (Liberati 2009).

Dealing with duplicate publications

In the case of duplicate publications and companion papers of a primary study, we will try to maximise yield of information by simultaneous evaluation of all available data. In cases of doubt, the original publication (usually the oldest version) will obtain priority.

Data extraction and management

Data extraction and data entry will be done independently by two different authors (EBV, LF). In case of disagreement, the opinion of a third author will be requested (APK). Authors of trials will be contacted if needed.

Assessment of risk of bias in included studies

Two authors (BVE, APK) will assess each trial independently. Possible disagreement will be resolved by consensus, or with consultation of a third party in case of disagreement. Interrater agreement for key bias indicators (e.g. allocation concealment, incomplete outcome data) will be calculated using the kappa statistic (Cohen 1960). In cases of disagreement, the rest of the group will be consulted and a judgement will be made based on consensus.

Risk of bias will be assessed using the Cochrane Collaboration’s tool (Higgins 2008). The following criteria will be used:

  • was the allocation sequence adequately generated?

  • was the allocation adequately concealed?

  • was knowledge of the allocated intervention adequately prevented during the study?

  • were incomplete outcome data adequately addressed?

  • are reports of the study free of suggestion of selective outcome reporting?

  • was the study apparently free of other problems that could put it at a high risk of bias?

A judgement of ‘Yes’ indicates low risk of bias, ‘No’ indicates high risk of bias, and ‘Unclear’ indicates unclear or unknown risk of bias. We will use the criteria for a judgement of ‘Yes’, ‘No’ and ‘Unclear’ for individual bias items as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). We will attach a 'risk of bias graph' figure and 'risk of bias summary' figure.

We will assess the impact of individual bias domains on study results at endpoint and study levels.

Measures of treatment effect

Dichotomous data will be expressed as risk ratio (RR), and risk difference (RD) with 95% confidence intervals (CI). Continuous data will be expressed as difference in means (MD) or standard difference in means (SMD) with 95% CI.

Unit of analysis issues

We will take into account the level at which randomisation occurred, such as cross‐over trials, cluster‐randomised trials and multiple observations for the same outcome.

Dealing with missing data

In case of any missing data or information, the authors of selected papers will be directly contacted for answers to the specific queries. Evaluation of important numerical data such as screened, randomised patients as well as intention‐to‐treat (ITT) and per‐protocol (PP) populations will be carefully performed. Attrition rates, for example drop‐outs, losses to follow‐up and withdrawals will be investigated. Issues of missing data and techniques to handle these (for example, last‐observation‐carried‐forward (LOCF)) will be critically appraised.

Assessment of heterogeneity

In the event of substantial clinical or methodological or statistical heterogeneity, study results will not be combined by means of meta‐analysis. Statistical heterogeneity will be identified by visual inspection of the forest plots, by using a standard Chi2 test and a significance level of α = 0.1, in view of the low power of such tests. Heterogeneity will be specifically examined with the I2 statistic, with categories 'might not be important' (0% to 40%), 'moderate' (30% to 60%), 'substantial' (50% to 90%) and 'considerable' (75% to 100%) (Higgins 2008). The I2 statistic will be used to judge the consistency of evidence across studies due to heterogeneity. When heterogeneity is found, we will attempt to determine potential reasons for it by examining individual study and subgroup characteristics. Methodological and clinical heterogeneity are also taken into account when assessing heterogeneity.

Assessment of reporting biases

Funnel plots will be used to assess for the potential existence of small study bias. There are a number of explanations for the asymmetry of a funnel plot (Sterne 2001). Therefore, we will carefully interpret results (Lau 2006).

Data synthesis

Data will be summarised statistically if they are available, sufficiently similar and of sufficient quality. Statistical analysis will be performed according to the statistical guidelines referenced in the newest version of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008).

Subgroup analysis and investigation of heterogeneity

We will define subgroups of major drug therapy groups according to the age, the use prior or after surgery and according to the route of administration (oral, subcutaneous or intramuscular) of the treatment if necessary.

Sensitivity analysis

We will perform sensitivity analyses in order to explore the influence of the following factors on effect size:

  • repeating the analysis excluding unpublished studies;

  • repeating the analysis taking account of risk of bias, as specified above;

  • repeating the analysis excluding any very long or large studies to establish how much they dominate the results;

  • repeating the analysis excluding studies using the following filters: diagnostic criteria, language of publication, source of funding (industry versus other), country.

The robustness of the results will also be tested by repeating the analysis using different measures of effects size (relative risk, odds ratio etc.) and different statistical models (fixed‐effect and random‐effect model).

Table 1. Drugs used for treatment of acromegaly

drug type and agent

starting dose

maximal dose

typical side effects

monitoring suggestions

preferred indication

Dopamine agonist

Cabergoline

1 mg/wk

per os

4 mg per week

nausea, GI cramps, gallstones

GH, IGF‐1

GH and prolactin co‐secreting tumours

Somatostatin analogous

Octreotide

50 mg sc t.i.d

200 mg t.i.d.

nausea, GI cramps, gallstones

GH, IGF‐I, ultrasonography of gallbladder (if symptomatic)

somatostatin analogous responsive tumours

Octreotide LAR

10 mg  i.m.
every 4 weeks

30 mg i.m.
every 4 weeks

nausea, GI cramps, gallstones 

GH, IGF‐I, ultrasonography of gallbladder (if symptomatic)

somatostatin analogous responsive tumours

Octreotide

60 mg i.m.
every 2 weeks

120 mg i.m.
every 7 days

nausea, GI cramps, gallstones 

GH, IGF‐I, ultrasonography of gallbladder (if symptomatic)

somatostatin analogous responsive tumours

Lanreotide autogel

60 mg i.m.
every 4 weeks

120 mg i.m.
every 4 weeks

nausea, GI cramps, gallstones 

GH, IGF‐I, ultrasonography of gallbladder (if symptomatic)

somatostatin analogous responsive tumours

GH antagonist

Pegvisomant

10 mg s.c. daily

40 mg daily 

headache, fatigue, abnormal liver enzymes

liver function test for 6 months then every 6 months,

MRI yearly, IGF‐1 only (not GH)

high IGF‐1 not responsive to somatostatin analogous therapy

GH: growth hormone; GI: gastrointestinal; IGF‐I: insulin‐like growth factor‐I; i.m.: intramuscular; LAR: long‐acting release; MRI: magnetic resonance imaging; s.c.: subcutaneous; t.i.d: three times a day

Figures and Tables -
Table 1. Drugs used for treatment of acromegaly
Navigate to table in Protocol
Table 2. Overview of study populations

study ID

intervention (I)
control (C)

[n] screened

[n] randomised

[n] safety

[n] ITT

[n] finishing study

[%] of randomised
participants
finishing study

comments

ID1

I1: Intervention 1
I2: Intervention 2
C1: Control 1
C2: Control 2

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

ID2

I1: Intervention 1
I2: Intervention 2
C1: Control 1
C2: Control 2

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

ID3

I1: Intervention 1
I2: Intervention 2
C1: Control 1
C2: Control 2

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

ID4

I1: Intervention 1
I2: Intervention 2
C1: Control 1
C2: Control 2

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

ID5

I1: Intervention 1
I2: Intervention 2
C1: Control 1
C2: Control 2

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

ID6

I1: Intervention 1
I2: Intervention 2
C1: Control 1
C2: Control 2

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

ID7

I1: Intervention 1
I2: Intervention 2
C1: Control 1
C2: Control 2

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

ID8

I1: Intervention 1
I2: Intervention 2
C1: Control 1
C2: Control 2

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

ID9

I1: Intervention 1
I2: Intervention 2
C1: Control 1
C2: Control 2

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

Total

I1:
I2:
C1:
C2:
Total:

I1:
I2:
C1:
C2:
Total:

ITT: intention‐to‐treat
Figures and Tables -
Table 2. Overview of study populations
Navigate to table in Protocol