Phase III, Randomized, Double Blind Trial Low Dose Tamoxifen Versus Placebo in Hormone Replacement Therapy (HRT) Users (HOT)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
European Institute of Oncology
ClinicalTrials.gov Identifier:
NCT01579734
First received: January 24, 2012
Last updated: June 17, 2014
Last verified: June 2014

January 24, 2012
June 17, 2014
March 2002
December 2014   (final data collection date for primary outcome measure)
breast cancer incidence [ Time Frame: 10 years ] [ Designated as safety issue: Yes ]
The primary objective is to assess if tamoxifen at a low dose reduces the incidence of breast cancer in healthy postmenopausal women undergoing or willing to initiate hormone replacement therapy (HRT), including the women who will eventually withdraw HRT during the 5 year intervention period and additional 5 years of follow up.
Same as current
Complete list of historical versions of study NCT01579734 on ClinicalTrials.gov Archive Site
Incidence of adverse events [ Time Frame: 10 years ] [ Designated as safety issue: Yes ]

Incidence of: other non-invasive breast disorders (i.e., LCIS, atypical hyperplasia) All other cancers (with special reference to endometrial cancer, colorectal cancer, ovarian cancer and melanoma).

Bone fractures Cardiovascular events Venous thromboembolic events Clinically manifest cataract Overall mortality

Same as current
Not Provided
Not Provided
 
Phase III, Randomized, Double Blind Trial Low Dose Tamoxifen Versus Placebo in Hormone Replacement Therapy (HRT) Users
The HOT Study: Hormone Replacement Therapy Opposed by Low Dose Tamoxifen. A Phase III Trial of Breast Cancer Prevention With Low Dose Tamoxifen in HRT Users.

The propose of this trial is to assess the effect of low dose tamoxifen for breast cancer prevention in HRT (Hormone Replacement Therapy)users.

While life expectancy has grown by approximately 30 years in the last century in western countries, the age at menopause has increased by 2-3 years only. Thus, women are exposed to postmenopausal symptoms and disorders related to estrogens drop for a considerable period of their lifetime. The management of these frequent disorders is an important public health issue. Although recent data from the WHI randomized trial have demonstrated that late postmenopausal women (mean age 63.3 years) taking oral conjugated equine estrogens and medroxyprogesterone acetate in a continuous combined regimen for prevention of coronary heart disease have an increased risk of developing cardiovascular disease and breast cancer, there is no question that treatment of menopausal symptoms with HRT (Hormone Replacement Therapy) in younger women aged around 50 years is a clinically beneficial treatment. This is even truer for women who enter menopause earlier than 45 years. It is prudent not to extend the results of the WHI trial, as such, to other forms of HRT preparations, routes, dosages and regimens or to early postmenopausal women with no apparent risk factors for CVD. Recently data from a non-randomized study, the Million Women Study, have suggested that oral combined regimens are associated with an increased and that transdermal estradiol does not increase more than oral treatment, and in general may be less harmful: for instance, transdermal estradiol has no effect on vascular inflammatory markers in contrast to the increase observed with oral CEE (conjugated equine estrogens). Notably, more recent data on the estrogens-alone group of the WHI trial show a lower breast cancer risk than the combination, suggesting a important role of progestin in the risk, and a significant reduction in colon cancer.

The increased risk of developing breast cancer, mostly estrogens receptor positive, particularly with the combination of estrogens and progestin, has been associated with an increased expression of estrogens receptors in the healthy breast tissue, thus leading to an enhanced sensitivity to the estrogens signal. Moreover, reproductive factors such as early menarche and delayed pregnancy are also associated with a higher risk of estrogens receptor (ER) positive breast cancer. Thus, the addition of a SERM may reduce the hormone growth-promoting effect on the breast gland. Tamoxifen has been investigated in four large cooperative phase III trials for breast cancer prevention in at-risk women. While the preliminary results of the Italian Tamoxifen Prevention Study in hysterectomized women showed no difference between arms, a recent update after 7 years of follow-up suggests that the combination of HRT and tamoxifen has a favorable effect and might even be synergistic. At a mean observation time of 81 months, a 25% reduction of breast cancer was noted in the tamoxifen arm compared with placebo (45 versus 34 events, Hazard Ratio, HR= 0.75, 95% CI, 0.48-1.18). While there is no difference in the subset of women who never took HRT before or during the trial (HR=1.01, 95% CI, 0.60-1.70), women, who at some point before or during the study, had ever taken HRT (n=1584) had fewer breast cancers in the tamoxifen arm (6 on tamoxifen versus 17 on placebo, HR=0.35, 95% CI, 0.14-0.89). Among the women continuously on HRT during the trial (n= 754), breast cancer events were 3 for women on tamoxifen versus 11 for those on placebo, respectively (HR=0.30, 95% CI, 0.08-1.06). Notably, 76.9% of HRT users received transdermal unopposed ERT and further 6.5% took transdermal ERT combined with progestins. Importantly, recent result from the IBIS I trial indicate that there is no evidence that HRT use affects the tamoxifen benefit. Recent studies suggest that the standard dose of tamoxifen may be reduced to one quarter (5 mg day) without significant loss of its beneficial effects on circulating biomarkers, mostly reflecting cardiovascular risk. Moreover, the efficacy of doses as low as one twentieth of the standard 20 mg/day dose on breast cancer cell proliferation has been recently shown. Since the endometrial effect of tamoxifen is dependent on treatment duration and dose, a dose reduction might reduce the risk of endometrial malignancies, while retaining its preventive efficacy. On the other hand, the addition of HRT containing progestins could further minimize the risk of endometrial cancer associated with tamoxifen. Moreover, estrogen should reduce the incidence of vasomotor and uro-genital symptoms, which are a major reason for tamoxifen withdrawal in prevention studies. In the NSABP trial, women aged 50 or younger demonstrated no significantly increased incidence of severe adverse events, including endometrial cancer and, even more importantly, venous thromboembolic events (VTE). One possible explanation for the lack of severe toxicity in premenopausal women is the concomitant presence of adequate circulating estrogens levels which prevent tamoxifen from acting as an estrogens agonist on these target tissues. Notably, in the IBIS I trial, no significant excess of endometrial cancer and VTE was noted in the women on HRT who were allocated to tamoxifen compared to placebo.

The above background provides the rationale for a phase III chemoprevention trial in postmenopausal healthy women HRT users and Tamoxifen: the HOT Study (Hormone replacement therapy Opposed by low dose Tamoxifen).

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Prevention
Breast Cancer
  • Drug: Tamoxifen
    1 tablet, 5 mg / day for 5 years
    Other Name: Nolvadex, Istubal, Valodex
  • Drug: Placebo
    1 tablet day for 5 years
  • Placebo Comparator: Placebo
    1 tablet day for 5 years
    Intervention: Drug: Placebo
  • Active Comparator: Tamoxifen
    Tamoxifen 5 mg, (1 tablet) day for 5 years
    Intervention: Drug: Tamoxifen
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
1884
December 2015
December 2014   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Postmenopausal women candidates to HRT for control of menopausal symptoms or prevention of postmenopausal disorders. women currently undergoing HRT for any duration; (women off HRT for 1 year or longer are considered de novo users);
  • negative bilateral mammography (within the last 6 months);
  • written informed consent.

Exclusion Criteria:

Any type of malignancy, with the exclusion of CIN and non-melanoma skin cancer;

  • active proliferative disorders of the endometrium such as atypical hyperplasia, history of active endometriosis, unresected polyps, symptomatic myomata;
  • alterations of metabolic, liver, renal and cardiac grade 2 function (NCI criteria grade 2 or higher);
  • any type of retinal disorders, severe cataract and glaucoma;
  • presence of significant risk factors for venous events, including immobilization within the last 3 months for longer than 2 weeks following surgery or trauma, history of estrogen-associated and "sine causa" superficial phlebitis, deep venous thrombophlebitis or other significant VTE (pulmonary embolism, stroke, etc.);
  • use of tamoxifen, raloxifene or other SERMs within the last 4 weeks;
  • anticoagulant therapy in progress (heparin or dicoumarol);
  • active infections;
  • severe psychiatric disorders or inability to comply to the protocol procedures; any other factor that at the investigator's discretion contraindicates the use of either tamoxifen or HRT.
Female
18 Years to 80 Years
No
Contact information is only displayed when the study is recruiting subjects
Italy
 
NCT01579734
IEO S51/200
Yes
European Institute of Oncology
European Institute of Oncology
Not Provided
Study Chair: Umberto Veronesi, MD European Institute of Oncology
European Institute of Oncology
June 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP