Clinical Trial Results:
A Phase II, open-label, ophthalmological external investigator-blinded, single-center, randomized, superiority, no profit, pilot clinical trial to evaluate the effects of atorvastatin on Graves' Orbitopathy (GO) in hypercholesterolemic patients with moderate-to-severe and active GO subjected to intravenous glucocorticoid therapy: the STAGO study

Trial information Top of page
Trial identification
Sponsor protocol code	STAGO
Additional study identifiers
ISRCTN number	-
US NCT number	NCT03110848
WHO universal trial number (UTN)	-
Sponsors
Sponsor organisation name	University of Pisa
Sponsor organisation address	Via Paradisa, 2, Pisa, Italy,
Public contact	U.O. Endocrinologia 1, AOUP, 0039 050997346, michele.marino@med.unipi.it
Scientific contact	U.O. Endocrinologia 1, AOUP, 0039 050997346, michele.marino@med.unipi.it
Sponsor organisation name	University of Pisa
Sponsor organisation address	Via Paradisa 2, Pisa, Italy,
Public contact	Michele Marinò, University of Pisa, 0039 05997346, michele.marino@unipi.it
Scientific contact	Michele Marinò, University of Pisa, 0039 05997346, michele.marino@unipi.it
Sponsor organisation name	University of Pisa
Sponsor organisation address	Via Paradisa 2, Pisa, Italy, 56124
Public contact	Michele Marinò, University of Pisa, 0039 0597346, michele.marino@unipi.it
Scientific contact	Michele Marinò, University of Pisa, 0039 05997346, michele.marino@unipi.it
Paediatric regulatory details
Is trial part of an agreed paediatric investigation plan (PIP)	No
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Results analysis stage
Analysis stage	Final
Date of interim/final analysis	03 May 2021
Is this the analysis of the primary completion data?	Yes
Primary completion date	30 Apr 2021
Global end of trial reached?	Yes
Global end of trial date	30 Apr 2021
Was the trial ended prematurely?	No
General information about the trial
Main objective of the trial	To investigate the effect of atorvastatin treatment on the overall outcome of Graves’ Orbitopathy at 24 weeks, in hypercolesterolemic patients with Graves’ disease and moderately severe, active Graves’ Orbitopathy to be treated with intravenous glucocorticoids .
Protection of trial subjects	Omeprazole 20 mg once a day for the first 12 weeks of the study alongside the intravenous methylprednisolone treatment. Omeprazole was administered to counter side-effects of the intravenous methylprednisolone regimen.
Background therapy	-
Evidence for comparator	-
Actual start date of recruitment	01 Jul 2020
Long term follow-up planned	No
Independent data monitoring committee (IDMC) involvement?	No
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled	Italy: 88
Worldwide total number of subjects	88
EEA total number of subjects	88
Number of subjects enrolled per age group
In utero	0
Preterm newborn - gestational age < 37 wk	0
Newborns (0-27 days)	0
Infants and toddlers (28 days-23 months)	0
Children (2-11 years)	0
Adolescents (12-17 years)	0
Adults (18-64 years)	60
From 65 to 84 years	28
85 years and over	0

Trial information Top of page

Subject disposition Top of page
Recruitment
Recruitment details	Patients were recruited consecutively over a 6 month period and randomly assigned (1:1) in 11 randomisation blocks of eight patients to receive methylprednisolone and atorvastatin (ST group) or methylprednisolone alone (NST group; the control group).
Pre-assignment
Screening details	119 participants were screened for eligibility. Among them, 31 subjects were excluded according to the inclusion and exclusion criteria of the study (for more details, please see the paper attached to the trial information page of this form)
Pre-assignment period milestones
Number of subjects started	88
Number of subjects completed	88
Period 1
Period 1 title	baseline period (overall period)
Is this the baseline period?	Yes
Allocation method	Randomised - controlled
Blinding used	Not blinded
Blinding implementation details	Only the ophthalmological investigator was blinded.
Arms
Are arms mutually exclusive	Yes
Arm title	methylprednisolone and atorvastatin (ST group)
Arm description	Patients received intravenous methylprednisolone plus atorvastatin. Intravenous methylprednisolone was administered according to a previously described protocol: 500 mg once a week for 6 weeks followed by 250 mg once a week for another 6 weeks (cumulative dose 4·5 g; appendix p 8). Atorvastatin was administered orally with a dosage of 20 mg once a day for 24 weeks.
Arm type	Experimental
Investigational medicinal product name	atorvastatin
Investigational medicinal product code
Other name
Pharmaceutical forms	Tablet
Routes of administration	Oral use
Dosage and administration details	20 mg once a day for 24 weeks
Arm title	metylprednisolone (NST group)
Arm description	Patients received intravenous methylprednisolone, according to a previously described protocol: 500 mg once a week for 6 weeks followed by 250 mg once a week for another 6 weeks (cumulative dose 4·5 g; appendix p 8). Patients in the ST group also received 20 mg oral atorvastatin once a day for 24 weeks.
Arm type	Active comparator
Investigational medicinal product name	atorvastatin
Investigational medicinal product code
Other name
Pharmaceutical forms	Tablet
Routes of administration	Oral use
Dosage and administration details	20 mg once a day for 24 weeks
Investigational medicinal product name	methylprednisolone
Investigational medicinal product code
Other name
Pharmaceutical forms	Dispersion for injection/infusion
Routes of administration	Intravenous bolus use
Dosage and administration details	500 mg/week
Investigational medicinal product name	methylprednisolone
Investigational medicinal product code
Other name
Pharmaceutical forms	Dispersion for injection/infusion
Routes of administration	Intravenous bolus use
Dosage and administration details	500 mg/week
Number of subjects in period 1 methylprednisolone and atorvastatin (ST group) metylprednisolone (NST group) Started 44 44 Completed 44 44

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups
Reporting group title	methylprednisolone and atorvastatin (ST group)
Reporting group description	Patients received intravenous methylprednisolone plus atorvastatin. Intravenous methylprednisolone was administered according to a previously described protocol: 500 mg once a week for 6 weeks followed by 250 mg once a week for another 6 weeks (cumulative dose 4·5 g; appendix p 8). Atorvastatin was administered orally with a dosage of 20 mg once a day for 24 weeks.
Reporting group title	metylprednisolone (NST group)
Reporting group description	Patients received intravenous methylprednisolone, according to a previously described protocol: 500 mg once a week for 6 weeks followed by 250 mg once a week for another 6 weeks (cumulative dose 4·5 g; appendix p 8). Patients in the ST group also received 20 mg oral atorvastatin once a day for 24 weeks.
Reporting group values methylprednisolone and atorvastatin (ST group) metylprednisolone (NST group) Total Number of subjects 44 44 88 Age categorical Units: Subjects     Adults (18-75 years) 44 44 88 Age continuous Units: years     arithmetic mean (standard deviation) 55.3 ( 9.2 ) 52.4 ( 11.2 ) - Gender categorical Units: Subjects     Female 32 29 61     Male 12 15 27
Subject analysis sets
Subject analysis set title	ITT population
Subject analysis set type	Intention-to-treat
Subject analysis set description	All the subjects who completed at least the 12-week visit.
Subject analysis sets values ITT population Number of subjects 80 Age categorical Units: Subjects     Adults (18-75 years) 80 Age continuous Units: years     arithmetic mean (standard deviation) ( ) Gender categorical Units: Subjects     Female     Male

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	methylprednisolone and atorvastatin (ST group)
Reporting group description	Patients received intravenous methylprednisolone plus atorvastatin. Intravenous methylprednisolone was administered according to a previously described protocol: 500 mg once a week for 6 weeks followed by 250 mg once a week for another 6 weeks (cumulative dose 4·5 g; appendix p 8). Atorvastatin was administered orally with a dosage of 20 mg once a day for 24 weeks.
Reporting group title	metylprednisolone (NST group)
Reporting group description	Patients received intravenous methylprednisolone, according to a previously described protocol: 500 mg once a week for 6 weeks followed by 250 mg once a week for another 6 weeks (cumulative dose 4·5 g; appendix p 8). Patients in the ST group also received 20 mg oral atorvastatin once a day for 24 weeks.
Subject analysis set title	ITT population
Subject analysis set type	Intention-to-treat
Subject analysis set description	All the subjects who completed at least the 12-week visit.

End points Top of page

Primary: overall outcome of Graves' orbitopathy Top of page
End point title	overall outcome of Graves' orbitopathy
End point description
End point type	Primary
End point timeframe	24 weeks
End point values methylprednisolone and atorvastatin (ST group) metylprednisolone (NST group) Number of subjects analysed 41 39 Units: 21/41     responders 21 11
Statistical analysis title	fisher exact test
Comparison groups	methylprednisolone and atorvastatin (ST group) v metylprednisolone (NST group)
Number of subjects included in analysis	80
Analysis specification	Pre-specified
Analysis type	superiority
P-value	< 0.05
Method	Fisher exact
Parameter type	AR
Confidence interval

Primary: overall outcome of Graves' orbitopathy Top of page

Adverse events Top of page
Adverse events information
Timeframe for reporting adverse events	Follow up period
Assessment type	Systematic
Dictionary used for adverse event reporting
Dictionary name	MedDRA
Dictionary version	16.1
Reporting groups
Reporting group title	ST group
Reporting group description	-
Reporting group title	NST group
Reporting group description	-
Serious adverse events ST group NST group Total subjects affected by serious adverse events      subjects affected / exposed 0 / 44 (0.00%) 0 / 44 (0.00%)      number of deaths (all causes) 0 0      number of deaths resulting from adverse events 0 0
Frequency threshold for reporting non-serious adverse events: 2%
Non-serious adverse events ST group NST group Total subjects affected by non serious adverse events      subjects affected / exposed 12 / 44 (27.27%) 14 / 44 (31.82%) Vascular disorders Hypertension      subjects affected / exposed 1 / 44 (2.27%) 1 / 44 (2.27%)      occurrences all number 1 1 Hot flush      subjects affected / exposed 1 / 44 (2.27%) 1 / 44 (2.27%)      occurrences all number 1 1 face swelling      subjects affected / exposed 1 / 44 (2.27%) 0 / 44 (0.00%)      occurrences all number 1 0 Cardiac disorders palpitations      subjects affected / exposed 1 / 44 (2.27%) 2 / 44 (4.55%)      occurrences all number 1 2 Gastrointestinal disorders Dyspepsia      subjects affected / exposed 0 / 44 (0.00%) 1 / 44 (2.27%)      occurrences all number 0 1 Gastritis      subjects affected / exposed 0 / 44 (0.00%) 1 / 44 (2.27%)      occurrences all number 0 1 abdominal disconfort      subjects affected / exposed 1 / 44 (2.27%) 0 / 44 (0.00%)      occurrences all number 1 0 Hepatobiliary disorders liver enzymes increasing      subjects affected / exposed 0 / 44 (0.00%) 1 / 44 (2.27%)      occurrences all number 0 1 Skin and subcutaneous tissue disorders Eczema      subjects affected / exposed 1 / 44 (2.27%) 0 / 44 (0.00%)      occurrences all number 1 0 rush      subjects affected / exposed 0 / 44 (0.00%) 1 / 44 (2.27%)      occurrences all number 0 1 Psychiatric disorders sleeping disorders      subjects affected / exposed 1 / 44 (2.27%) 1 / 44 (2.27%)      occurrences all number 1 1 depressive mood      subjects affected / exposed 0 / 44 (0.00%) 1 / 44 (2.27%)      occurrences all number 0 1 Musculoskeletal and connective tissue disorders Myositis      subjects affected / exposed 1 / 44 (2.27%) 0 / 44 (0.00%)      occurrences all number 1 0 Infections and infestations Cystitis      subjects affected / exposed 2 / 44 (4.55%) 1 / 44 (2.27%)      occurrences all number 2 1 Oral fungal infection      subjects affected / exposed 1 / 44 (2.27%) 0 / 44 (0.00%)      occurrences all number 1 0 Herpes simplex      subjects affected / exposed 0 / 44 (0.00%) 1 / 44 (2.27%)      occurrences all number 0 1 Metabolism and nutrition disorders Hyperglycaemia      subjects affected / exposed 1 / 44 (2.27%) 1 / 44 (2.27%)      occurrences all number 1 1 Weight increased      subjects affected / exposed 0 / 44 (0.00%) 1 / 44 (2.27%)      occurrences all number 0 1

Adverse events Top of page

More information Top of page
Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? No
Interruptions (globally)
Were there any global interruptions to the trial? No
Limitations and caveats
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
None reported

More information Top of page